Laura Waters

British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015

Writing Group Duncan Churchill, Chair, Royal Sussex County Hospital, Brighton, UK Laura Waters, Vice Chair, Mortimer Market Centre, London, UK Nadia Ahmed, Mortimer Market Centre, London, UK Brian Angus, University of Oxford, UK Marta Boffito, Chelsea and Westminster Hospital, London, UK Mark Bower, Chelsea and Westminster Hospital, London, UK David Dunn, University College London, UK Simon Edwards, Central and North West London NHS Foundation Trust, UK Carol Emerson, Royal Victoria Hospital, Belfast, UK Sarah Fidler, Imperial College School of Medicine at St Mary’s, London, UK †Martin Fisher, Royal Sussex County Hospital, Brighton, UK Rob Horne, University College London, UK Saye Khoo, University of Liverpool, UK Clifford Leen, Western General Hospital, Edinburgh, UK Nicola Mackie, Imperial College Healthcare NHS Trust, London, UK Neal Marshall, Royal Free Hospital NHS Trust, London, UK Fernando Monteiro, UK-CAB Mark Nelson, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK

The Impact of HIV Tropism on Decreases in CD4 Cell Count, Clinical Progression, and Subsequent Response to a First Antiretroviral Therapy Regimen

BACKGROUND Human immunodeficiency virus (HIV) uses 2 distinct chemokine receptors, CCR5 (R5) or CXCR4 (X4), during entry. Viruses may be R5 tropic, X4 tropic, or dual/mixed (D/M) tropic. R5-tropic virus predominates at high CD4 cell counts, with the number of X4-tropic strains increasing as CD4 cell count decreases. METHODS We investigated the relationship between tropism and decreases in CD4 cell count before antiretroviral therapy initiation, the frequency of clinical events, and responses to antiretroviral therapy in a cohort of treatment-naive patients. RESULTS Four hundred two treatment-naive patients underwent tropism determination; 326 harbored R5-tropic virus, and 76 harbored X4- or D/M-tropic virus. After adjustment for baseline characteristics, the rate of decrease in CD4 cell count was significantly greater in patients infected with X4- or D/M-tropic virus at 12 months (P=.026). Two hundred twenty-nine individuals infected with R5-tropic virus and 60 individuals infected with X4- or D/M-tropic virus commenced antiretroviral therapy between tropism testing and the time of data analysis. Time to viral suppression and the proportion of patients achieving viral suppression were similar at 6, 12, and 24 months. CD4 cell count increases were similar. Clinical events were significantly more common in the group infected with X4- or D/M-tropic virus. Multivariate analysis demonstrated a relative risk of experiencing a clinical event of 2.56 (95% confidence interval, 1.37-4.76; P=.003) among patients infected with X4- or D/M-tropic virus. CONCLUSIONS The presence of D/M- or X4-tropic virus has a deleterious effect on CD4 cell count decrease and risk of clinical disease. Response to standard antiretroviral therapy is not affected by viral tropism.

Prospective HLA-B*5701 screening and abacavir hypersensitivity : a single centre experience

Suspected hypersensitivity is the main reason for the early discontinuation of abacavir. After the observation that the risk of hypersensitivity correlated with ethnicity, the presence of the HLA allele B*5701 was found to be the strongest retrospective predictor of hypersensitivity. Two prospective cohorts have since demonstrated a significant reduction in abacavir hypersensitivity rates with the use of prospective human leukocyte antigen screening. We describe our experience of prospective HLA-B*5701 testing and the impact on rates of abacavir hypersensitivity.

A phase Iv, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine

Background:Two nucleoside reverse transcriptase inhibitors (NRTIs) and efavirenz (EFV) is a recommended initial regimen for HIV-1. Most EFV-related central nervous system (CNS) toxicity resolves early though symptoms may persist; we studied switching to etravirine (ETR) in these individuals. Methods:A randomized, double-blind trial in patients with viral suppression but ongoing CNS adverse events after more than 12 weeks EFV. Patients received 2NRTI/EFV/ETR-placebo (delayed switch) or 2NRTI/ETR/EFV-placebo (immediate switch) for 12 weeks followed by 12-week open-label phase (2NRTI/ETR). Primary end-point was percentage with G2-4 CNS adverse events at 12 weeks. Results:Thirty-eight men; 20/18 were randomized to immediate switch/delayed switch; median CD4 was 444/498 cells/μl, respectively. Baseline CNS adverse events were similar. Nineteen immediate switch patients completed follow-up (one lost to follow-up) and 13 on delayed switch (two lost to follow-up, two withdrawn consent, one adverse event). Immediate switch G2-4 CNS adverse event: 90% at baseline, 60% at week 12 (P = 0.041). Delayed switch G2-4 CNS adverse event: 88.9% at baseline, 81.3% at week 12 (P = ns). Combined (both arms) percentage decline in G2-4 CNS adverse event after 12 weeks of ETR was significant for overall adverse events, insomnia, abnormal dreams and nervousness (P = 0.009, 0.016, 0.001, and 0.046, respectively). All participants on study maintained HIV-RNA below 50 and median week 24 CD4 was 593 and 607 cells/μl on immediate switch and delayed switch. Two participants experienced new G3-4 adverse events [delayed switch: G3 flatulence on EFV); immediate switch: G4 viral URTI on ETR (SAE)]. Conclusion:Switching EFV to ETR led to a significant reduction in overall G2-4 CNS adverse events, including insomnia, abnormal dreams and nervousness as individual adverse event. Lack of improvement for some events suggests other causative factors.

Discontinuation of Atripla as first-line therapy in HIV-1 infected individuals.

Background:Central nervous system (CNS) adverse events are common with initiation of efavirenz, but these are often described as transient. We aimed to describe the outcomes of individuals commencing Atripla (Gilead Sciences Inc, Foster City, California; Bristol-Myers Squibb Co, Princeton, New Jersey, USA) as a first-line regimen. Methods:We performed a retrospective case-based analysis of all individuals within our HIV cohort who had received Atripla as their first antiretroviral combination. In individuals who discontinued Atripla data was collected on evolution of adverse events. Results:Four hundred and seventy-two individuals commenced Atripla as first-line therapy at 12 months, 383 individuals (81%) remained on Atripla with 98% achieving HIV-1 RNA less than 50 copies/ml (on treatment analysis). CNS toxicity was the commonest reason for switching therapy in 63 (71%) cases. The median duration of first reported CNS toxicity was 27 days (IQR 7–104 days) and the commonest reported symptoms were nightmares or vivid dreams in 28 (44%), insomnia in 27 (43%) and depression in 22 (35%). In those with CNS toxicity, six (10%) switched at 0–4 weeks, four (6%) at 4–12 weeks, 30 (48%) at 12–52 weeks and 23 (36%) changed regimen 52–96 weeks after commencing Atripla. Among those with available documentation 25 of 63 (40%) had reported improvement or resolution of their CNS side effects. Discussion:One-fifth of all individuals commencing Atripla will need to switch therapy, often for adverse events. The commonest reason for switch in our cohort was CNS toxicity, which although it may develop shortly after initiation may persist, ultimately leading to discontinuation of Atripla months or years later.

Hepatitis C virus infection in HIV type 1-infected individuals does not accelerate a decrease in the CD4+ cell count but does increase the likelihood of AIDS-defining events

Human immunodeficiency virus type 1 (HIV-1) appears to adversely affect hepatitis C, but whether hepatitis C virus (HCV) has a reciprocal effect on HIV-1 infection remains a point of controversy. In a multivariate analysis of a cohort of 5832 individuals, we found that individuals coinfected with HCV and HIV-1 (prevalence of coinfection, 5.8%) had a CD4+ cell count that decreased at a rate similar to that for individuals infected with HIV-1 alone. However, coinfection was associated with a statistically significant increased likelihood of onset of an acquired immunodeficiency syndromedefining illness or developing a CD4+ cell count of <200 cells/mm3, compared with infection with HIV-1 alone (hazard ratio, 1.52; 95% confidence interval, 1.072.17). Patients who were naive to highly active antiretroviral therapy were significantly less likely to progress to either end point, because of their higher CD4+ cell counts. In conclusion, there was an increased number of adverse events in coinfected individuals, compared with individuals infected with HIV-1 alone.

British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012: BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of adults with HIV infection with antiretroviral therapy (ART). The scope includes: (i) guidance on the initiation of ART in those previously naïve to therapy; (ii)support of patients on treatment; (iii) management of patients experiencing virological failure; and (iv) recommendations in specific patient populations where other factors need to be taken into consideration. The guidelines are aimed at clinical professionals directly involved with and responsible for the care of adults with HIV infection and at community advocates responsible for promoting the best interests and care of HIV-positive adults. They should be read in conjunction with other published BHIVA guidelines.

Late HIV presentation: epidemiology, clinical implications and management

Late presentation of HIV is common and is associated with several adverse outcomes including an increased risk of clinical progression, blunted immune recovery on highly active antiretroviral therapy and a greater risk of drug toxicity. Late presenters may have higher rates of poor adherence, exacerbated by the same factors that contribute to their late diagnosis, such as lack of knowledge about HIV and the benefits of highly active antiretroviral therapy. We review the definitions of, risk factors for and subsequent impact of late presentation. Evidence regarding how and when to start antiretroviral therapy, and with which agents, will be discussed, as well as issues surrounding vaccination and opportunistic infection prophylaxis for individuals with a low CD4 count. Finally, strategies to increase HIV testing uptake to reduce late presentation will be summarized.

HIV-1 superinfection.

Purpose of review This review describes the nature and frequency of HIV-1 superinfection and provides advice regarding counselling of patients in accordance with national guidelines. Recent findings Recent studies have demonstrated conflicting results, from no superinfection to an incidence of over 18%. We discuss the difficulties comparing studies due to population and methodological differences. Summary HIV-infected individuals should be counselled that there is risk of superinfection at all stages of HIV, but this is unlikely to be clinically significant unless transmission of resistance occurs. The risk may be as high as the risk of new incident infection in the presence of on-going exposure.

Population pharmacokinetics of ritonavir-boosted atazanavir in HIV-infected patients and healthy volunteers

Objectives The aim of this study was to develop and validate a population pharmacokinetic model to: (i) describe ritonavir-boosted atazanavir concentrations (300/100 mg once daily) and identify important covariates; and (ii) evaluate the predictive performance of the model for lower, unlicensed atazanavir doses (150 and 200 mg once daily) boosted with ritonavir (100 mg once daily). Methods Non-linear mixed effects modelling was applied to determine atazanavir pharmacokinetic parameters, inter-individual variability (IIV) and residual error. Covariates potentially related to atazanavir pharmacokinetics were explored. The final model was assessed by means of a visual predictive check for 300/100, 200/100 and 150/100 mg once daily. Results Forty-six individuals were included (30 HIV-infected). A one-compartment model with first-order absorption and lag-time best described the data. Final estimates of apparent oral clearance (CL/F), volume of distribution (V/F) and absorption rate constant [relative standard error (%) and IIV (%)] were 7.7 L/h (5, 29), 103 L (13, 48) and 3.4 h−1 (34, 154); a lag-time of 0.96 h (1) was determined. Ritonavir area under the curve (AUC0–24) was the only significant covariate. Overall, 94%–97% of observed concentrations were within the 95% prediction intervals for all three regimens. Conclusions A population pharmacokinetic model for ritonavir-boosted atazanavir has been developed and validated. Ritonavir AUC0–24 was significantly associated with atazanavir CL/F. The model was used to investigate other, particularly lower, ritonavir-boosted atazanavir dosing strategies.