Adrian Palfreeman

Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study.

BACKGROUNDnThe SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral suppression [VS] group). In the DC group, participants started ART when the CD4+ cell count was <250 cells/microL. Clinical outcomes in participants not receiving ART at entry inform the early use of ART.nnnMETHODSnPatients who were either ART naive (n=249) or who had not been receiving ART for >or= 6 months (n=228) were analyzed. The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death); (ii) OD (fatal or nonfatal); (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non-AIDS-defining cancers) and non-OD deaths; and (iv) the composite of outcomes (ii) and (iii).nnnRESULTSnA total of 477 participants (228 in the DC group and 249 in the VS group) were followed (mean, 18 months). For outcome (iv), 21 and 6 events occurred in the DC (7 in ART-naive participants and 14 in those who had not received ART for >or= 6 months) and VS (2 in ART-naive participants and 4 in those who had not received ART for 6 months) groups, respectively. Hazard ratios for DC vs. VS by outcome category were as follows: outcome (i), 3.47 (95% confidence interval [CI], 1.26-9.56; p=.02); outcome (ii), 3.26 (95% CI, 1.04-10.25; p=.04); outcome (iii), 7.02 (95% CI, 1.57-31.38; p=.01); and outcome (iv), 4.19 (95% CI, 1.69-10.39; p=.002 ).nnnCONCLUSIONSnInitiation of ART at CD4+ cell counts >350 cells/microL compared with <250 cells/microL may reduce both OD and serious non-AIDS events. These findings require validation in a large, randomized clinical trial.Background. The SMART study randomized 5472 human immunodeficiency virus (HIV)-infected patients with CD4 + cell counts >350 cells/μL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral supression [VS] group). In the DC group, participants started ART when the CD4 + cell count was 350 cells/μL compared with <250 cells/μL may reduce both OD and serious non-AIDS events. These findings require validation in a large, randomized clinical trial.

British HIV Association guidelines for the management of HIV infection in pregnant women 2012

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of human immunodeficiency virus (HIV)-positive pregnant women in the UK. The scope includes guidance on the use of antiretroviral therapy (ART) both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration,such as coinfection with other agents. The guidelines are aimed at clinical professionals directly involved with, and responsible for, the care of pregnant women with HIV infection.

Pneumonia in HIV-infected persons - Increased risk with cigarette smoking and treatment interruption

RATIONALEnBacterial pneumonia is a major cause of morbidity for HIV-infected persons and contributes to excess mortality in this population.nnnOBJECTIVESnTo evaluate the frequency and risk factors for occurrence of bacterial pneumonia in the present era of potent antiretroviral therapy.nnnMETHODSnWe evaluated data from a randomized trial of episodic antiretroviral therapy. The study, Strategies for Management of Antiretroviral Therapy, enrolled 5,472 participants at 318 sites in 33 countries. Study patients had more than 350 CD4 cells at baseline. Diagnosis of bacterial pneumonia was confirmed by a blinded clinical-events committee.nnnMEASUREMENTS AND MAIN RESULTSnDuring a mean follow-up of 16 months, 116 participants (2.2%) developed at least one episode of bacterial pneumonia. Patients randomized to receive episodic antiretroviral therapy were significantly more likely to develop pneumonia than patients randomized to receive continuous antiretroviral therapy (hazard ratio, 1.55; 95% confidence interval, 1.07-2.25; P = 0.02). Cigarette smoking was a major risk factor: Current-smokers had more than an 80% higher risk of pneumonia compared with never-smokers (hazard ratio, 1.82; 95% confidence interval, 1.09-3.04; P = 0.02). Participants who were on continuous HIV treatment and were current smokers were three times more likely to develop bacterial pneumonia than nonsmokers. Current smoking status was significant, but a past history of smoking was not.nnnCONCLUSIONSnBacterial pneumonia is a major source of morbidity, even for persons on potent antiretroviral therapy, including those with high CD4 cells. Efforts to reduce this illness should stress the importance of uninterrupted antiretroviral therapy and attainment and/or maintenance of nonsmoking status.

British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review)

Emtricitabine/tenofovir/rilpivirine as a single‐tablet regimen (STR) is widely used without licence in treatment‐experienced patients. The purpose of this retrospective observational study was to assess viral suppression of ART‐experienced patients switching to STR.

Outcomes in the first year after initiation of first-line HAART among heterosexual men and women in the UK CHIC Study

BACKGROUNDnWe analysed the influence of gender on use and outcomes of first-line HAART in a UK cohort.nnnMETHODSnAnalyses included heterosexuals starting HAART from 1998-2007 with pre-treatment CD4(+) T-cell count<350 cells/mm(3) and viral load (VL)>500 copies/ml. Virological suppression (<50 copies/ml), virological rebound (>500 copies/ml), CD4(+) T-cell counts at 6 and 12 months, clinical events and treatment discontinuation/switch in the first year of HAART were compared using linear, logistic and Cox regression.nnnRESULTSnCompared with women (n=2,179), men (n=1,487) were older and had lower CD4(+) T-cell count and higher VL at start of HAART. Median follow-up was 3.8 years (IQR 2.0-6.2). At 6 and 12 months, 72.7% and 75.3% had VL≤50 copies/ml, with no large differences between genders at either time after adjustment for confounders (6 months, OR 0.92 [95% CI 0.76-1.13]; 12 months, OR 1.06 [95% CI 0.85-1.31]). Overall, 79.4% patients achieved virological suppression and 19.2% experienced virological rebound, without gender differences, although men had an increased risk of rebound after excluding pregnant women (adjusted relative hazard [RH] 1.33 [95% CI 1.04-1.71]). Mean CD4(+) T-cell count increases at 6 and 12 months were, respectively, 112 and 156 cells/mm(3) overall, with mean differences between men and women of -14.6 cells/mm(3) (95% CI -24.6--4.5) and -12.1 cells/mm(3) (95% CI -24.4-0.2) at 6 and 12 months, respectively. Clinical progression was similar in men and women, but men were less likely to experience treatment discontinuation/switch (adjusted RH 0.72 [95% CI 0.63-0.83]).nnnCONCLUSIONSnDespite higher discontinuation rates among women, men had an increased risk of virological rebound and slightly poorer CD4(+) T-cell count responses. Identifying the reasons underlying treatment discontinuation/switch may help optimize treatment strategies for both genders.

Interleukin-6, high sensitivity C-reactive protein, and the development of type 2 diabetes among HIV-positive patients taking antiretroviral therapy

Background:HIV infection is associated with increased levels of inflammatory markers. Inflammation is hypothesized to play a role in the development of type 2 diabetes. Data addressing this issue among HIV-positive participants are limited. Methods:A cohort of 3695 participants without diabetes, taking antiretroviral therapy and with an average CD4+ count of 523 cells/mm3, were followed for an average of 4.6 years. Diabetes risk associated with baseline levels of high sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) was assessed using Cox proportional hazards regression models. Analyses considered baseline levels of factors associated with diabetes risk and HIV-related measures. Results:One hundred thirty-seven patients developed diabetes requiring drug treatment during follow-up (8.18 per 1000 person-years). Median levels of IL-6 and hsCRP were significantly higher among those who developed diabetes compared with those who did not: 3.45 versus 2.50 pg/mL for IL-6 and 4.91 versus 3.29 µg/mL for hsCRP (P < 0.001). Adjusted hazard ratios associated with a doubling of IL-6 and hsCRP were 1.29 (95% confidence interval: 1.08 to 1.55; P = 0.005) and 1.22 (95% confidence interval: 1.10 to 1.36; P < 0.001), respectively. Body mass index (P < 0.001), age (P = 0.013), coinfection with hepatitis B or C (P = 0.03), nonsmoking status (P = 0.034), and use of lipid-lowering treatment (P = 0.008) were also associated with an increased risk of diabetes. Conclusions:These findings indicate that low-grade systemic inflammation is an underlying factor in the pathogenesis of diabetes.

Platelet count kinetics following interruption of antiretroviral treatment

Objectives:To investigate the mechanisms of platelet kinetics in the Strategies for Management of Antiretroviral Therapy (SMART) study that demonstrated excess mortality with CD4 guided episodic antiretroviral therapy (ART) drug conservation compared with continuous treatment viral suppression. Follow-up analyses of stored plasma samples demonstrated increased activation of both inflammatory and coagulation pathways after stopping ART. Design:SMART patients from sites that determined platelets routinely. Methods:Platelet counts were retrospectively collected from 2206 patients from visits at study entry, and during follow-up. D-dimer levels were measured at study entry, month 1, and 2. Results:Platelet levels decreased in the drug conservation group following randomization, but remained stable in the viral suppression group [median (IQR) decline from study entry to month 4: −24u200a000/&mgr;l (−54u200a000 to 4000) vs. 3000 (−22u200a000 to 24u200a000), respectively, Pu200a<u200a0.0001)] and the rate of developing thrombocytopenia (<100u200a000/&mgr;l) was significantly higher in the drug conservation vs. the viral suppression arm (unadjusted drug conservation/viral suppression [HR (95%CI)u200a=u200a1.8 (1.2–2.7)]. The decline in platelet count among drug conservation participants on fully suppressive ART correlated with the rise in D-dimer from study entry to either month 1 or 2 (ru200a=u200a−0.41; Pu200a=u200a0.02). Among drug conservation participants who resumed ART 74% recovered to their study entry platelet levels. Conclusion:Interrupting ART increases the risk of thrombocytopenia, but reinitiation of ART typically reverses it. Factors contributing to declines in platelets after interrupting ART may include activation of coagulation pathways or HIV-1 replication itself. The contribution of platelets in HIV-related procoagulant activity requires further study.

Failure to achieve a CD4+ cell count response on combination antiretroviral therapy despite consistent viral load suppression

Objective:To assess CD4+ cell count recovery in people severely immunosuppressed at start of antiretroviral therapy (ART) who achieve and maintain viral load suppression. Methods:Eligible participants from the UK Collaborative HIV Cohort Study started ART with at least three drugs after 1 January 2000. Participants were required to have pre-ART CD4+ cell count below 100u200acells/&mgr;l, at least 2 years of follow-up on ART, have achieved viral load suppression (⩽50u200acopies/ml) by 9 months after starting ART and to have maintained this throughout follow-up. Participants were further required to be regularly engaged with care. We calculated the proportion of people who failed to achieve a CD4+ cell count of more than 100, 150, 200, 350 and 500u200acells/&mgr;l by the time of the last follow-up, or 5 years from start of ART, whichever occurred first (censoring date). Results:Of the 400 participants [median (interquartile range) pre-ART CD4+ cell count of 38 (14–65) cells/&mgr;l], 2 (0.5%), 8 (2%), 28 (7%), 131 (33%) and 259 (65%) failed to achieve a CD4+ cell count of more than 100, 150, 200, 350 and 500u200acells/&mgr;l, by the censoring date, respectively. Kaplan–Meier estimates of the proportion of people reaching each CD4+ cell count threshold after 1 year on ART were 88, 70, 50, 14 and 3%, respectively, and after 3 years on ART, 98, 95, 90, 59 and 25%, respectively. Median (interquartile range) follow-up on ART was 3.9 (2.7–4.8) years. Conclusion:Given a person with pre-ART CD4+ cell count below 100u200acells/&mgr;l survives and maintains consistent viral load suppression on ART, there is over a 90% chance of reaching a CD4+ cell count above 200u200acells/&mgr;l by 3 years.

Inflammation-Related Morbidity and Mortality Among HIV-Positive Adults: How Extensive Is It?

Objective: To determine the rate of grade 4, potentially life-threatening events not attributable to AIDS, cardiovascular disease (CVD), or non-AIDS cancer among participants on antiretroviral therapy and to describe associations of these events with interleukin-6 (IL-6) and D-dimer. Design: Cohort study. Methods: HIV-infected participants on antiretroviral therapy (N = 3568) with an HIV-RNA level ⩽ 500 copies/mL were followed for grade 4, AIDS, CVD, non-AIDS cancer, and all-cause mortality events. Grade 4 events were further classified masked to biomarker levels as reflecting chronic inflammation–related disease (ChrIRD) or not (non-ChrIRD). Associations of baseline IL-6 and D-dimer with events were studied using Cox models. Results: Over a median follow-up of 4.3 years, 339 participants developed a grade 4 event (22.9 per 1000 person-years); 165 participants developed a ChrIRD grade 4 event (10.7 per 1000 person-years). Grade 4 events were more common than AIDS (54 participants), CVD (132), and non-AIDS cancer (80) events, any of which developed in 252 participants (17.1 per 1000 person-years). Grade 4 and AIDS events were associated with similar risks of death. Higher IL-6 [hazard ratio (HR) = 1.19 per doubling of biomarker; P = 0.003] and D-dimer (HR = 1.23; P < 0.001) levels were associated with an increased risk of grade 4 events. IL-6 associations were stronger for ChrIRD (HR = 1.38; P < 0.001) than non-ChrIRD grade 4 events (HR = 1.11; P = 0.21). Conclusions: Morbidity and mortality associated with activation of inflammatory and coagulation pathways include conditions other than AIDS, CVD, and non-AIDS cancer events. Effective inflammation-dampening interventions could greatly affect the health of people with HIV.

Uptake and outcome of combination antiretroviral therapy in men who have sex with men according to ethnic group: the UK CHIC Study

Background:We investigated differences in retention in HIV care and uptake of combination antiretroviral therapy (cART) and treatment outcomes between different ethnic men who have sex with men (MSM) groups. Methods:MSM subjects with known ethnicity and ≥1 day follow-up from 1996 to 2009 in the UK Collaborative HIV Cohort Study were included. Black and minority ethnic (BME) men were categorized as: black; Indian/Pakistani/Bangladeshi; other Asian/Oriental; and other/mixed. Logistic regression was used to identify factors associated with treatment initiation within the 6 months after each CD4 count. HIV viral load, CD4 counts, discontinuation/switch of a drug in the initial cART regimen, and development of a new AIDS event/death at 6 and 12 months were also analyzed. Results:Of 16,406 MSM, 1818 (11.0%) were BME; 892 (49.1%) black, 139 (7.6%) Indian/Pakistani/Bangladeshi, 254 (13.9%) other Asian/Oriental, 532 (29.2%) other/mixed. The proportion of MSM with no follow-up after HIV diagnosis was higher among BME than white MSM (3.4% vs. 2.2%, P = 0.002). Permanent loss to follow-up was highest in the other/mixed and lowest in Indian/Pakistani/Bangladeshi groups (P = 0.02). Six thousand three hundred thirty-eight MSM initiated first cART from January 1, 2000, to January 1, 2009. In multivariable analyses, BME MSM were 18% less likely to initiate cART than white MSM with similar CD4 counts [adjusted odds ratio 0.82 (95% confidence interval: 0.74 to 0.91), P = 0.0001]. However, once on cART, there were no differences in virological, immunological, and clinical outcomes. Conclusions:This study demonstrates that despite BME MSM being a “minority within a minority” for those HIV infected, there are few ethnic disparities in access to and treatment outcomes in our setting.