Nicola Mackie

Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial

Summary Background Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir–emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. Methods PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). Findings We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64–96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3–11·3). 13 men (90% CI 9–23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. Interpretation In this high incidence population, daily tenofovir–emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. Funding MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.

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

British HIV Association guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals 2011.

1. Levels of evidence 1.1 Reference 2. Introduction 3. Auditable targets 4. Table summaries 4.1 Initial diagnosis 4.2 Assessment of ART‐naïve individuals 4.3 ART initiation 4.4 Initial assessment following commencement of ART 4.5 Routine monitoring on ART 4.6 References 5. Newly diagnosed and transferring HIV‐positive individuals 5.1 Initial HIV‐1 diagnosis 5.2 Tests to determine whether acquisition of HIV infection is recent 5.3 Individuals transferring care from a different HIV healthcare setting 5.4 Communication with general practitioners and shared care 5.5 Recommendations 5.6 References 6. Patient history 6.1 Initial HIV‐1 diagnosis 6.2 Monitoring of ART‐naïve patients 6.3 Pre‐ART initiation assessment 6.4 Monitoring individuals established on ART 6.5 Assessment of adherence 6.6 Recommendations 6.7 References 7. Examination 7.1 Recommendations 8. Identifying the need for psychological support 8.1 References 9. Assessment of immune status 9.1 CD4 T cell counts 9.2 CD4 T cell percentage 9.3 References 10. HIV viral load 10.1 Initial diagnosis/ART naïve 10.2 Post ART initiation 10.3 Individuals established on ART 10.4 Recommendations 10.5 References 11. Technical aspects of viral load testing 11.1 References 12. Viral load kinetics during ART and viral load ‘blips’ 12.1 References 13. Proviral DNA load 13.1 References 14. Resistance testing 14.1 Initial HIV‐1 diagnosis 14.2 ART‐naïve 14.3 Post treatment initiation 14.4 ART‐experienced 14.5 References 15. Subtype determination 15.1 Disease progression 15.2 Transmission 15.3 Performance of molecular diagnostic assays 15.4 Response to therapy 15.5 Development of drug resistance 15.6 References 16. Other tests to guide use of specific antiretroviral agents 16.1 Tropism testing 16.2 HLA B*5701 testing 16.3 References 17. Therapeutic drug monitoring 17.1 Recommendations 17.2 References 18. Biochemistry testing 18.1 Introduction 18.2 Liver function 18.3 Renal function 18.4 Dyslipidaemia in HIV‐infected individuals 18.5 Other biomarkers 18.6 Bone disease in HIV‐infected patients 18.7 References 19. Haematology 19.1 Haematological assessment and monitoring 19.2 Recommendations 19.3 References 20. Serology 20.1 Overview 20.2 Hepatitis viruses 20.3 Herpes viruses 20.4 Measles and rubella 20.5 Cytomegalovirus (CMV) 20.6 References 21. Other microbiological screening 21.1 Tuberculosis screening 21.2 Toxoplasma serology 21.3 Tropical screening 21.4 References 22. Sexual health screening including anal and cervical cytology 22.1 Sexual history taking, counselling and sexually transmitted infection (STI) screening 22.2 Cervical and anal cytology 22.3 Recommendations 22.4 References 23. Routine monitoring recommended for specific patient groups 23.1 Women 23.2 Older age 23.3 Injecting drug users 23.4 Individuals coinfected with HBV and HCV 23.5 Late presenters 23.6 References Appendix

British HIV Association, BASHH and FSRH guidelines for the management of the sexual and reproductive health of people living with HIV infection 2008

A Fakoya, H Lamba, N Mackie, R Nandwani, A Brown, EJ Bernard, C Gilling-Smith, C Lacey, L Sherr, P Claydon, S Wallage and B Gazzard British HIV Association (BHIVA), BHIVA Secretariat, Mediscript Ltd, 1 Mountview Court, 310 Friern Barnet Lane, London N20 OLD, British Association for Sexual Health and HIV (BASHH), Royal Society of Medicine, 1 Wimpole Street, London W1G OAE and Faculty of Sexual and Reproductive Health of the Royal College of Obstetricians and Gynaecologists (FSRH), 27 Sussex Place, Regent’s Park, London NW1 4RG, UK

Antiretroviral therapy is associated with sexual dysfunction and with increased serum oestradiol levels in men

Our objective was to determine the relationship between highly active antiretroviral therapy (HAART), serum total oestradiol and sexual dysfunction in HIV-infected men. Sexual difficulties were recorded prospectively in a cohort of HIV-negative (or unknown status) gay/bisexual men (MSM) and a cohort of HIV-infected men. The HIV-infected men were divided into those on and not on HAART and by sexuality. Serum total oestradiol and testosterone levels were evaluated where possible. One hundred HIV-negative MSM and 73 HIV-infected men (88% MSM) were analysed. Low libido and erectile dysfunction (ED) were reported in the control group in 2% and 10% respectively. This compared to a prevalence of 26% for both problems in HIV-infected MSM not taking HAART. In those MSM on HAART reduced libido was noted in 48% and ED in 25%. In the group of men taking HAART the mean oestradiol level was 228 pmol/L and was significantly above normal limits. Low libido and ED are more commonly reported in HIV-infected men compared to gay men of negative or unknown status. HAART is associated with a higher prevalence of lack of sexual desire and raised serum oestradiol levels.

Clinical implications of stopping nevirapine-based antiretroviral therapy: relative pharmacokinetics and avoidance of drug resistance

To determine the pharmacokinetics of cessation of nevirapine (NVP) in order to design clinical protocols which will reduce the risk of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs).

Antiretroviral Drug Resistance in HIV-1-Infected Patients with Low-Level Viremia

This study characterized the prevalence and patterns of antiretroviral-drug-resistance mutations according to plasma human immunodeficiency virus type 1 (HIV-1) RNA load in a large population of patients with HIV-1 infection who underwent testing for resistance mutations in routine clinical practice. HIV-1 genotypic resistance test results with linked clinical data were obtained from national resistance and clinical databases in the United Kingdom. Among 7861 tests, detection of > or =1 resistance mutation was most frequent at viral loads of 300-10,000 copies/mL and decreased statistically significantly at viral loads of >10,000 copies/mL. Major resistance mutations were commonly detected in the subset of tests that were performed among patients with viral loads of <1000 copies/mL (1001 [12.7%] of 7861 tests). We conclude that HIV-1 genotypic resistance testing is informative for patients with low viral loads.

Time trends in drug resistant HIV-1 infections in the United Kingdom up to 2009: multicentre observational study.

Objective To evaluate whether the prevalence of HIV-1 transmitted drug resistance has continued to decline in infections probably acquired within the United Kingdom. Design Multicentre observational study. Setting All UK public laboratories conducting tests for genotypic HIV resistance as a part of routine care. Participants 14 584 patients infected with HIV-1 subtype B virus, who were first tested for resistance before receiving antiretroviral therapy between January 2002 and December 2009. Main outcome measure Prevalence of transmitted drug resistance, defined as one or more resistance mutations from the surveillance list recommended by the World Health Organization. Results 1654 (11.3%, 95% confidence interval 10.8% to 11.9%) patients had one or more mutations associated with transmitted HIV-1 drug resistance; prevalence was found to decline from 15.5% in 2002 to 9.6% in 2007, followed by a slight increase to 10.9% in 2009 (P=0.21). This later rise was mainly a result of increases in resistance to nucleos(t)ide reverse transcriptase inhibitors (from 5.4% in 2007 to 6.6% in 2009, P=0.24) and protease inhibitors (1.5% to 2.1%, P=0.12). Thymidine analogue mutations, including T215 revertants, remained the most frequent mutations associated with nucleos(t)ide reverse transcriptase inhibitors, despite a considerable fall in stavudine and zidovudine use between 2002 and 2009 (from 29.4% of drug regimens in 2002 to 0.8% in 2009, from 47.9% to 8.8%, respectively). Conclusions The previously observed decline in the prevalence of transmitted drug resistance in HIV-1 infections probably acquired in the UK seems to have stabilised. The continued high prevalence of thymidine analogue mutations suggests that the source of this resistance may be increasingly from patients who have not undergone antiretroviral therapy and who harbour resistant viruses. Testing of all newly diagnosed HIV-1 positive people should be continued.

Factors associated with cerebrospinal fluid HIV RNA in HIV infected subjects undergoing lumbar puncture examination in a clinical setting

BACKGROUND Cerebrospinal fluid (CSF) HIV RNA load may be associated with central nervous system (CNS) disease in HIV infected subjects. We investigated parameters associated with CSF HIV RNA within a large clinical cohort. METHODS All HIV infected subjects undergoing CSF examination including assessment of CSF HIV RNA at St. Marys Hospital, London, UK between January 2008 and October 2010 were included. Parameters associated with a detectable CSF HIV RNA load were assessed using linear regression modelling. CSF viral escape was defined as CSF RNA >0.5 log(10) copies/mL greater than plasma HIV RNA and >200 copies/mL where plasma HIV RNA <50 copies/mL. RESULTS Of 142 subjects, 99 were receiving antiretroviral therapy (ART). Plasma HIV RNA was <50 copies/mL in 69 subjects. CSF examination was performed for investigation of presumed HIV encephalopathy (IxHE, n = 57), other CNS diseases considered HIV related (n = 39), syphilis (n = 20) and CNS presentations not considered HIV related (n = 26). CSF viral escape was present in 30/142 (21%) subjects overall and in 9/69 (13%) of those on ART with undetectable plasma HIV RNA. Overall, plasma HIV RNA load was significantly associated with detectable CSF HIV RNA (p ≤ 0.001). In subjects with plasma HIV RNA <50 copies/mL, only CNS penetration effectiveness (CPE, 2008) score of <2 was significantly associated with detectable CSF HIV RNA (p = 0.044). In patients undergoing LP for IxHE both plasma HIV RNA and CPE scores were independently associated with detectable CSF HIV RNA (p = 0.019 & 0.003 respectively) which was not observed in subjects undergoing CSF examination for other medical reasons. CONCLUSIONS In a clinical setting, CSF viral escape is observed frequently in 21% of subjects and is associated with different parameters depending on the clinical scenario.

Clinical epidemiology of HIV-associated end-stage renal failure in the UK.

Objective:To describe the clinical epidemiology of HIV-associated end-stage renal failure (HIV/ESRF) from 1998 to 2007 in the United Kingdom. Design:Observational cohort study. Setting:Seven leading HIV centres and affiliated renal clinics in the United Kingdom. Participants:A total of 21 951 patients in whom renal function was measured. Main outcome measure:Development of end-stage renal failure (ESRF) as defined by initiation of permanent renal replacement therapy (pRRT). Results:Sixty-eight (0.31%) patients had HIV/ESRF, 44 (64.7%) of whom were black. The prevalence of ESRF in black patients increased over time from 0.26% in 1998–1999 to 0.92% in 2006–2007 (P for trend = 0.001). Overall 5-year survival from starting pRRT was 70.3%, and significantly better for black patients compared to those of other ethnicities (85.2 vs. 43.4%, P = 0.001). In multivariable analysis, black ethnicity was associated with a higher risk of ESRF [HR 6.93, 95% confidence interval (CI) 3.56, 13.48], whereas a higher current CD4 cell count was associated with reduced risk (HR: 0.83, 95% CI 0.76, 0.95) per 50 cells higher). No association was seen between current viral load or current highly active antiretroviral therapy (HAART) status and ESRF. On the basis of these observations, we estimate that 231 HIV-infected patients required pRRT in the United Kingdom in 2007, and an HIV prevalence of 0.51% among the United Kingdom pRRT recipients in that year. Conclusion:The prevalence of HIV/ESRF increased during the HAART era to reach nearly 1% in black patients, in whom favourable survival rates were observed. Earlier HIV diagnosis will be an important strategy to stem the rising trend of HIV/ESRF.