The impact of COVID-19 on HIV testing in the UK's first Fast-Track HIV city.

OBJECTIVES: To describe the impact that the COVID-19 pandemic has had on HIV testing in Brighton and Hove, United Kingdom. METHODS: All HIV tests performed in Brighton and Hove from January 2016 to June 2021 were extracted, de-duplicated and anonymized. Analysis was performed to compare the monthly numbers of tests and diagnoses before and during the pandemic across different services. RESULTS: The number of patients having tests for HIV in sexual health services (SHS) decreased by 64% in April 2020, followed by a recovery to baseline levels by the start of 2021. Similarly, the monthly number of diagnoses decreased drastically after April 2020, with almost half of diagnoses made by SHS in 2020 occurring in the three pre-pandemic months of the year. 'Self-sampling', used more by women and younger patients, has contributed significantly to the recovery. The number of patients tested in secondary care was seemingly unaffected by the pandemic. However, testing numbers were reduced in specialist services, whereas in the emergency department (ED) testing increased four-fold (most notably in the elderly) without finding any cases. General practice saw decreases in both the number of HIV tests performed and the number of new diagnoses made, which had not returned to baseline by June 2021. DISCUSSION: The COVID-19 pandemic has had a large impact on the number of HIV tests performed in Brighton and Hove with sizeable decreases in the number of patients tested likely leading to 'missed' diagnoses. By June 2021 testing had still not returned to normal across the city.

Chemsex and antiretroviral prescribing in an HIV cohort in Brighton, UK.

OBJECTIVES: Chemsex has been reported among men who have sex with men (MSM) living with HIV. There have been concerns about potentially harmful drug-drug interactions between chemsex drugs and antiretroviral therapy (ritonavir and cobicistat). We aimed to describe the prevalence and patterns of chemsex users in our HIV clinic population and to evaluate antiretroviral prescribing among chemsex users. METHODS: We undertook a cross-sectional study of patients attending our HIV clinic between January 2019 and December 2020. We collected data on patients who disclosed recent recreational drug use including chemsex in the previous 3 months. RESULTS: In all, 2202/2501 (88%) patients were asked about recreational drug use and 514 (23%) disclosed recreational drug use. Eighty-two (4%) of these disclosed recent chemsex; 73 (89%) used crystal methamphetamine, 51 (62%) used gamma-hydroxybutyrate (GHB)/gamma-butyrolactone (GBL), 55 (67%) reported poly-drug use and 63 (76%) reported injecting drug use. The chemsex users were all cis-male MSM and were significantly older (53 vs. 46 years, p < 0.0001), and more likely to have had previous syphilis (73% vs. 28%, p < 0.0001) than patients reporting non-chemsex drug use. All chemsex users were prescribed antiretrovirals and 74 (90%) had an undetectable HIV viral load; 31 (38%) patients were taking either ritonavir (N = 12) or cobicistat (N = 19) as part of their antiretroviral regimen and this was similar to other patients attending for HIV care [31/82 (38%) vs. 768/2419 (31%), p = 0.25]. CONCLUSIONS: The prevalence of chemsex users among our HIV clinic attendants is 4%, and 38% of these were prescribed either ritonavir or cobicistat. Chemsex use should be a factor in antiretroviral therapy decision-making to avoid potential harm.

A phase IV randomised, open-label pilot study to evaluate switching from protease-inhibitor based regimen to Bictegravir/Emtricitabine/Tenofovir Alafenamide single tablet regimen in Integrase inhibitor-naïve, virologically suppressed HIV-1 infected adults harbouring drug resistance mutations (PIBIK study): study protocol for a randomised trial.

BACKGROUND: Currently recommended boosted protease-inhibitor (bPI) regimens may be associated with increased risk of cardiovascular or chronic kidney diseases; in addition, boosted regimens are particularly associated with drug-drug interactions. Since both cardiovascular and renal disease, and polypharmacy, are common in ageing people with HIV, there is a need for alternative efficacious regimens. bPI-based regimens are often the treatment of choice for individuals with pre-treatment or treatment-acquired resistance but it is plausible that carefully selected HIV-positive individuals with drug resistance, who are virologically suppressed on their current bPI regimen, could maintain virological efficacy when switched to bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) fixed dose combination (FDC). METHODS/DESIGN: A phase IV, investigator-initiated, multicentre, open label pilot, randomised two-arm study to assess the safety and efficacy of switching from bPI regimen to B/F/TAF single tablet regimen in integrase inhibitor-naïve, virologically suppressed adults with HIV-1 infection harbouring drug resistance mutations. Eligible individuals will either continue on their bPI regimen or switch to B/F/TAF FDC. After 24 weeks, all participants in the bPI arm will be switched to B/F/TAF and followed for a further 24 weeks and all participants will be followed for 48 weeks. The primary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24 using pure virologic response whilst the secondary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at Week 48. Other secondary outcome measures include between arm comparisons of drug resistance at virological failure, safety and tolerability and patient-reported outcome measures. DISCUSSION: We aim to provide preliminary evidence of the efficacy of switching to B/F/TAF in patients with virological suppression on a bPI-based regimen who harbour select drug resistance mutations. TRIAL REGISTRATION: ISRCTN 44453201 , registered 19 June 2019 and EudraCT 2018-004732-30.

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.

Prevalence of and risk factors for gout in HIV-positive adults: A case-control study.

Gout is the most common inflammatory arthritis worldwide. Its principal risk factor is hyperuricaemia. While gout has been described in HIV patients and numerous more outdated anti-retroviral therapies (ARTs) have been implicated, there have been few recent studies. Our case-control study investigated the prevalence of and risk factors for gout in an established HIV cohort. Cases were identified from database searches using key search terms, with two age- and gender-matched controls. These were compared for demographic factors, co-morbidities, HIV factors and ART exposure. Forty-five cases with gout were identified (point prevalence 2.2%). All were male and were more likely than controls to be of black African origin. Hypertension was associated with an almost five-fold increased gout risk (OR 4.8, 95% CI 1.8-12.4). No individual drug or ART class was associated with gout in this study but exposure to non-nucleoside reverse transcriptase inhibitors had a significantly protective effect against the risk of gout (OR 0.3, 95% CI 0.1-0.9). Our data suggest that gout is common in HIV patients and that the traditional risk factors, especially hypertension, play a key role. Gout and hyperuricaemia should be regarded as a biomarker of cardiovascular disease in HIV patients as they are in the general population.

An association between K65R and HIV-1 subtype C viruses in patients treated with multiple NRTIs.

Objectives: HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis. Patients and methods: We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs. Results: Subtype B patients ( n = 3410) were mostly MSM (78%) and those with subtype C ( n = 810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55-2.62, P < 0.001). Conclusions: Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated.

Assessment and management of musculoskeletal disorders among patients living with HIV.

HIV is a global pandemic. However, anti-retroviral therapy has transformed the prognosis and, providing compliance is good, a normal life expectancy can be anticipated. This has led to increasing numbers of people with chronic prevalent, treated infection living to older ages. Musculoskeletal pain is commonly reported by HIV patients and, with resumption of near-normal immune function, HIV-infected patients develop inflammatory rheumatic diseases that require assessment and management in rheumatology clinics. Moreover, it is becoming apparent that avascular necrosis and osteoporosis are common comorbidities of HIV. This review will contextualize the prevalence of musculoskeletal symptoms in HIV, informed by data from a UK-based clinic, and will discuss the management of active inflammatory rheumatic diseases among HIV-infected patients taking anti-retroviral therapy, highlighting known drug interactions.

No Evidence That HIV-1 Subtype C Infection Compromises the Efficacy of Tenofovir-Containing Regimens: Cohort Study in the United Kingdom.

Concern has been expressed that tenofovir-containing regimens may have reduced effectiveness in the treatment of human immunodeficiency virus type 1 (HIV-1) subtype C infections because of a propensity for these viruses to develop a key tenofovir-associated resistance mutation. We evaluated whether subtype influenced rates of virological failure in a cohort of 8746 patients from the United Kingdom who received a standard tenofovir-containing first-line regimen and were followed for a median of 3.3 years. In unadjusted analyses, the rate of failure was approximately 2-fold higher among patients infected with subtype C virus as compared to those with subtype B virus (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.50-2.31; P < .001). However, the increased risk was greatly attenuated in analyses adjusting for demographic and clinical factors (adjusted HR, 1.14; 95% CI, .83-1.58; P = .41). There were no differences between subtypes C and subtypes non-B and non-C in either univariate or multivariate analysis. These observations imply there is no intrinsic effect of viral subtype on the efficacy of tenofovir-containing regimens.

Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIV-1 subtype B and non-subtype B receiving a salvage regimen.

OBJECTIVES: The objective of this study was to improve the prediction of the impact of HIV-1 protease mutations in different viral subtypes on virological response to darunavir. METHODS: Darunavir-containing treatment change episodes (TCEs) in patients previously failing PIs were selected from large European databases. HIV-1 subtype B-infected patients were used as the derivation dataset and HIV-1 non-B-infected patients were used as the validation dataset. The adjusted association of each mutation with week 8 HIV RNA change from baseline was analysed by linear regression. A prediction model was derived based on best subset least squares estimation with mutational weights corresponding to regression coefficients. Virological outcome prediction accuracy was compared with that from existing genotypic resistance interpretation systems (GISs) (ANRS 2013, Rega 9.1.0 and HIVdb 7.0). RESULTS: TCEs were selected from 681 subtype B-infected and 199 non-B-infected adults. Accompanying drugs were NRTIs in 87%, NNRTIs in 27% and raltegravir or maraviroc or enfuvirtide in 53%. The prediction model included weighted protease mutations, HIV RNA, CD4 and activity of accompanying drugs. The model's association with week 8 HIV RNA change in the subtype B (derivation) set was R(2) = 0.47 [average squared error (ASE) = 0.67, P < 10(-6)]; in the non-B (validation) set, ASE was 0.91. Accuracy investigated by means of area under the receiver operating characteristic curves with a binary response (above the threshold value of HIV RNA reduction) showed that our final model outperformed models with existing interpretation systems in both training and validation sets. CONCLUSIONS: A model with a new darunavir-weighted mutation score outperformed existing GISs in both B and non-B subtypes in predicting virological response to darunavir.

Is HIV Painful? An Epidemiologic Study of the Prevalence and Risk Factors for Pain in HIV-infected Patients.

OBJECTIVES: To evaluate the prevalence, impact, and risk factors for pain among a cohort of human immunodeficiency virus (HIV)-infected adults treated with combination antiretroviral therapy if indicated according to current guidelines. METHODS: This was a cross-sectional epidemiological observational study. All patients attending 1 HIV-outpatient center in the United Kingdom in a 10-month period were eligible. Patients completed a validated questionnaire enquiring about demographics, HIV factors, and symptoms of pain. RESULTS: Of 1050 eligible participants, 859 (82%) completed a questionnaire. The 1-month period prevalence of pain lasting >1 day was 62.8% among whom 63% reported current pain. The prevalence of pain at most anatomic sites was broadly similar to that observed in population studies using the same questionnaires except that we found considerably higher rates of foot/ankle pain. The median duration of pain was 3 years (range, 0 to 51 y) and the median pain score was 5.0 on an 11-point visual analogue score. Over 40% of people in pain had consulted their primary care physician and >20% were taking analgesics daily. Independent risk factors for current pain were older age (P=0.001), time since diagnosis of HIV infection (P=0.001), and receipt of a protease inhibitor-based regimen (P=0.04). DISCUSSION: Pain, and notably foot/ankle pain, is common among adults living with prevalent HIV and is associated with substantial morbidity and health care utilization.

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.

Older HIV-infected individuals present late and have a higher mortality: Brighton, UK cohort study.

BACKGROUND: Initiating therapy with a low CD4 cell count is associated with a substantially greater risk of disease progression and death than earlier initiation. We examined factors associated with late presentation of HIV using the new European consensus definition (CD4 cell count <350 cells/mm3) and mortality. METHODS: Patients newly diagnosed with HIV infection at a UK clinic were recruited from January 1996 to May 2010. Factors associated with late presentation were assessed using logistic regression. Factors associated with mortality rates were analysed using Poisson regression. RESULTS: Of the 1536 included in the analysis, 86% were male and 10% were aged 50 years and older. Half the cohort (49%) had a CD4 cell count below 350 cells/mm3 at presentation ("late presentation"). The frequency of late presentation was highest in those aged 50 years or older and remained unchanged over time (64.3% in 1996-1998 and 65.4% in 2008-2010). In contrast, among those aged less than 50 years, the proportion with late presentation decreased over time (57.1% in 1996-1998 and 38.5% in 2008-2010). Other factors associated with late presentation were African ethnicity and being a male heterosexual.The mortality rate was 15.47/1000 person-years (pyrs) (95%-CI: 13.00-18.41). When compared with younger adults, older individuals had a higher mortality, after adjusting for confounders (rate ratio (RR) = 2.87; 95%-CI: 1.88-4.40). CONCLUSIONS: Older adults were more likely to present late and had a higher mortality. Initiatives to expand HIV testing in clinical and community setting should not neglect individuals aged over 50.

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.

British HIV Association 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.