Attenuated humoral responses in HIV after SARS-CoV-2 vaccination linked to B cell defects and altered immune profiles.

We assessed a cohort of people living with human immunodeficiency virus (PLWH) (n = 110) and HIV negative controls (n = 64) after 1, 2 or 3 SARS-CoV-2 vaccine doses. At all timepoints, PLWH had significantly lower neutralizing antibody (nAb) titers than HIV-negative controls. We also observed a delayed development of neutralization in PLWH that was underpinned by a reduced frequency of spike-specific memory B cells (MBCs). Improved neutralization breadth was seen against the Omicron variant (BA.1) after the third vaccine dose in PLWH but lower nAb responses persisted and were associated with global MBC dysfunction. In contrast, SARS-CoV-2 vaccination induced robust T cell responses that cross-recognized variants in PLWH. Strikingly, individuals with low or absent neutralization had detectable functional T cell responses. These PLWH had reduced numbers of circulating T follicular helper cells and an enriched population of CXCR3+CD127+CD8+T cells after two doses of SARS-CoV-2 vaccination.

Attenuated humoral responses in HIV infection after SARS-CoV-2 vaccination are linked to global B cell defects and cellular immune profiles.

People living with HIV (PLWH) on suppressive antiretroviral therapy (ART) can have residual immune dysfunction and often display poorer responses to vaccination. We assessed in a cohort of PLWH (n=110) and HIV negative controls (n=64) the humoral and spike-specific B-cell responses following 1, 2 or 3 SARS-CoV-2 vaccine doses. PLWH had significantly lower neutralizing antibody (nAb) titers than HIV-negative controls at all studied timepoints. Moreover, their neutralization breadth was reduced with fewer individuals developing a neutralizing response against the Omicron variant (BA.1) relative to controls. We also observed a delayed development of neutralization in PLWH that was underpinned by a reduced frequency of spike-specific memory B cells (MBCs) and pronounced B cell dysfunction. Improved neutralization breadth was seen after the third vaccine dose in PLWH but lower nAb responses persisted and were associated with global, but not spike-specific, MBC dysfunction. In contrast to the inferior antibody responses, SARS-CoV-2 vaccination induced robust T cell responses that cross-recognized variants in PLWH. Strikingly, a subset of PLWH with low or absent neutralization had detectable functional T cell responses. These individuals had reduced numbers of circulating T follicular helper cells and an enriched population of CXCR3 + CD127 + CD8 + T cells after two doses of SARS-CoV-2 vaccination, which may compensate for sub-optimal serological responses in the event of infection. Therefore, normalisation of B cell homeostasis could improve serological responses to vaccines in PLWH and evaluating T cell immunity could provide a more comprehensive immune status profile in these individuals and others with B cell imbalances.

Causes of hospitalisation among a cohort of people with HIV from a London centre followed from 2011 to 2018.

BACKGROUND: We describe the spectrum of ICD-10 classified causes for hospitalisations occurring between 2011 and 2018 in a cohort of people living with HIV (PLHIV). METHODS: This sub-study includes 798 PLHIV participating in the Antiretroviral, Sexual Transmission Risk and Attitudes (ASTRA) questionnaire study who were recruited from a large London centre. A medical record review identified the occurrence and causes of hospitalisation from the date of questionnaire completion (February-December 2011) until 1 June 2018. Up to five causes were classified by an HIV clinician using the ICD-10 system. RESULTS: There were 274 hospitalisations in 153 people (rate = 5.8/100 person-years; 95% CI: 5.1, 6.5). Causes were wide-ranging; the most common were circulatory (16.8%), digestive (13.1%), respiratory (11.7%), infectious diseases (11.0%), injury/poisoning (10.6%), genitourinary diseases (9.9%) and neoplasms (9.1%). A tenth (27/274) of hospitalisations were related to at least one AIDS-defining illness. Median duration of hospitalisation was 5 days (IQR 2-9). At the time of hospitalisation, median CD4 count was high (510 cells/µl; IQR: 315-739), while median CD4 nadir was relatively low (113 cells/µl; IQR: 40-239). At admission, half of individuals (51%) had a previous AIDS-defining illness and 21% had viral load > 50 copies/ml. Individuals admitted for infectious diseases were particularly likely to have unfavourable HIV-related clinical characteristics (low CD4, viral non-suppression, not on antiretroviral therapy (ART), previous AIDS). CONCLUSIONS: In the modern combination antiretroviral therapy era, the spectrum of causes of hospitalisation in PLHIV in the UK is wide-ranging, highlighting the importance of holistic care for PLHIV, including prevention, early detection and treatment of comorbidities.

Prospective association of social circumstance, socioeconomic, lifestyle and mental health factors with subsequent hospitalisation over 6-7 year follow up in people living with HIV.

BACKGROUND: Predictors of hospitalisation in people with HIV (PLHIV) in the contemporary treatment era are not well understood. METHODS: This ASTRA sub-study used clinic data linkage and record review to determine occurrence of hospitalisations among 798 PLHIV from baseline questionnaire (February to December 2011) until 1 June 2018. Associations of baseline social circumstance, socioeconomic, lifestyle, mental health, demographic and clinical factors with repeated all-cause hospitalisation from longitudinal data were investigated using Prentice-Williams-Peterson models. Associations were also assessed in 461 individuals on antiretroviral therapy (ART) with viral load ≤50 copies/ml and CD4 count ≥500 cells/ µl. FINDINGS: Rate of hospitalisation was 5.8/100 person-years (95% CI: 5.1-6.5). Adjusted for age, demographic group and time with diagnosed HIV, the following social circumstance, socioeconomic, lifestyle and mental health factors predicted hospitalisation: no stable partner (adjusted hazard ratio (aHR)=1.59; 95% CI=1.16-2.20 vs living with partner); having children (aHR=1.50; 1.08-2.10); non-employment (aHR=1.56; 1.07-2.27 for unemployment; aHR=2.39; 1.70-3.37 for sick/disabled vs employed); rented housing (aHR=1.72; 1.26-2.37 vs homeowner); not enough money for basic needs (aHR=1.82; 1.19-2.78 vs enough); current smoking (aHR=1.39; 1.02-1.91 vs never); recent injection-drug use (aHR=2.11; 1.30-3.43); anxiety symptoms (aHRs=1.39; 1.01-1.91, 2.06; 1.43-2.95 for mild and moderate vs none/minimal); depressive symptoms (aHRs=1.67; 1.17-2.38, 1.91; 1.30-2.78 for moderate and severe vs none/minimal); treated/untreated depression (aHRs=1.65; 1.03-2.64 for treated depression only, 1.87; 1.39-2.52 for depressive symptoms only; 1.53; 1.05-2.24; for treated depression and depressive symptoms, versus neither). Associations were broadly similar in those with controlled HIV and high CD4. INTERPRETATION: Social circumstance, socioeconomic disadvantage, adverse lifestyle factors and poorer mental health are strong predictors of hospitalisation in PLHIV, highlighting the need for targeted interventions and care. FUNDING: British HIV Association (BHIVA) Research Award (2017); SMR funded by a PhD fellowship from the Royal Free Charity.

Descriptive account of 18 adults with known HIV infection hospitalised with SARS-CoV-2 infection.

OBJECTIVE: To report on the clinical characteristics and outcome of 18 people living with HIV (PLWH) hospitalised with SARS-CoV-2 infection in a London teaching hospital. METHODS: The hospital notes of 18 PLWH hospitalised with SARS-CoV-2 infection were retrospectively reviewed alongside data concerning their HIV demographics from an established HIV Database. RESULTS: The majority (16/18) had positive PCR swabs for SARS-CoV-2, and two had negative swabs but typical COVID-19 imaging and history. Most were male (14/18, 78%), median age 63 years (range 47-77 years). Two-thirds were migrants, nine (50%) of Black, Asian and minority ethnicity (BAME). All were diagnosed with HIV for many years (range 8-31 years), and all had an undetectable HIV viral load (<40 copies/mL). The median CD4 prior to admission was 439 (IQR 239-651), and 10/16 (63%) had a CD4 nadir below 200 cells/mm3. Almost all (17/18) had been diagnosed with at least one comorbidity associated with SARS-CoV-2 prior to admission. 3/18 patients died. None received mechanical ventilation. Hospital stay and clinical course did not appear prolonged (median 9 days). CONCLUSIONS: Our data suggest that PLWH may not necessarily have prolonged or complex admissions to hospital when compared with the general hospital and national population admitted with COVID-19. Many had low nadir CD4 counts and potentially impaired functional immune restoration. The PLWH group was younger than generally reported for COVID-19, and the majority were male with multiple complex comorbidities. These patients had frequent contact with hospital settings increasing potential for nosocomial acquisition and increased risk of severe COVID-19.

The effect of HIV status on the frequency and severity of acute respiratory illness.

INTRODUCTION: Antiretroviral therapy has improved the health of people living with HIV (PLW-HIV), though less is known about how this impacts on acute respiratory illness. These illnesses are a common cause of ill health in the general population and any increase in their frequency or severity in PLW-HIV might have significant implications for health-related quality of life and the development of chronic respiratory disease. METHODS: In a prospective observational cohort study following PLW-HIV and HIV negative participants for 12 months with weekly documentation of any acute respiratory illness, we compared the frequency, severity and healthcare use associated with acute respiratory illnesses to determine whether PLW-HIV continue to have a greater frequency or severity of such illnesses despite antiretroviral therapy. RESULTS: We followed-up 136 HIV positive and 73 HIV negative participants for 12 months with weekly documentation of any new respiratory symptoms. We found that HIV status did not affect the frequency of acute respiratory illness: unadjusted incidence rates per person year of follow-up were 2.08 illnesses (95% CI 1.81-2.38) and 2.30 illnesses (1.94-2.70) in HIV positive and negative participants respectively, IRR 0.87 (0.70-1.07) p = 0.18. However, when acute respiratory illnesses occurred, PLW-HIV reported more severe symptoms (relative fold-change in symptom score 1.61 (1.28-2.02), p <0.001) and were more likely to seek healthcare advice (42% vs 18% of illnesses, odds ratio 3.32 (1.48-7.39), p = 0.003). After adjustment for differences in baseline characteristics, PLW-HIV still had higher symptom scores when unwell. CONCLUSIONS: HIV suppression with antiretroviral therapy reduces the frequency of acute respiratory illness to background levels, however when these occur, they are associated with more severe self-reported symptoms and greater healthcare utilisation. Exploration of the reasons for this greater severity of acute respiratory illness may allow targeted interventions to improve the health of people living with HIV. TRIAL REGISTRATION: ISRCTN registry (ISRCTN38386321).

Outcomes of domestic violence screening at an acute London trust: are there missed opportunities for intervention?

OBJECTIVES: Domestic violence screening is advocated in some healthcare settings. Evidence that it increases referral to support agencies or improves health outcomes is limited. This study aimed to (1) investigate the proportion of hospital patients reporting domestic violence, (2) describe characteristics and previous hospital attendances of affected patients and (3) assess referrals to an in-house domestic violence advisor from Camden Safety Net. DESIGN: A series of observational studies. SETTING: Three outpatient clinics at the Royal Free London NHS Foundation Trust. PARTICIPANTS: 10,158 patients screened for domestic violence in community gynaecology, genitourinary medicine (GUM) and HIV medicine clinics between 1 October 2013 and 30 June 2014. Also 2253 Camden Safety Net referrals over the same period. MAIN OUTCOME MEASURES: (1) Percentage reporting domestic violence by age group gender, ethnicity and clinic. (2) Rates of hospital attendances in the past 3 years for those screening positive and negative. (3) Characteristics, uptake and risk assessment results for hospital in-house domestic violence referrals compared with Camden Safety Net referrals from other sources. RESULTS: Of the 10,158 patients screened, 57.4% were female with a median age of 30 years. Overall, 7.1% reported ever-experiencing domestic violence, ranging from 5.7% in GUM to 29.4% in HIV services. People screening positive for domestic violence had higher rates of previous emergency department attendances (rate ratio (RR) 1.63, 95% CI 1.09 to 2.48), emergency inpatient admissions (RR 2.27, 95% CI 1.37 to 3.84) and day-case admissions (RR 2.03, 95% CI 1.23 to 3.43) than those screening negative. The 77 hospital referrals to the hospital-based domestic violence advisor during the study period were more likely to be taken up and to be classified as high risk than referrals from elsewhere. CONCLUSIONS: Selective screening for domestic violence in high-risk hospital clinic populations has the potential to identify affected patients and promote good uptake of referrals for in-house domestic violence support.

Detection of low-frequency K103N mutants after unstructured discontinuation of efavirenz in the presence of the CYP2B6 516 TT polymorphism.

OBJECTIVES: To measure antiretroviral drug plasma levels in newly diagnosed HIV-1 seropositive persons who presented with an undetectable plasma HIV-1 RNA load but gave no history of antiretroviral drug exposure and to determine the impact of interrupting undisclosed or unknown antiretroviral therapy on the emergence of drug resistance. PATIENTS AND METHODS: Five newly diagnosed, reportedly drug-naive HIV-1 seropositive persons were included in the study. Drug resistance was determined by population and clonal sequencing of reverse transcriptase and protease. CYP2B6 polymorphisms were assayed by real-time PCR allelic discrimination on pre-amplified exons. RESULTS: Efavirenz was detected in the plasma of one of the five persons coinciding with a viral load <40 copies/mL by two different assays. When efavirenz became undetectable, the viral load rebounded. The patient was CYP2B6-516T homozygous. Population sequencing showed wild-type subtype D virus, whereas clonal sequencing detected low-frequency (2%) K103N. The patient firmly denied antiretroviral exposure but described the use of Ugandan remedies. CONCLUSIONS: In migrating populations seeking HIV testing, careful and compassionate counselling is required to facilitate the disclosure of previous diagnosis and therapy. The use of remedies of dubious content should also be discussed and investigated.

Response to efavirenz-containing regimens in previously antiretroviral-naive HIV-positive patients: the role of gender.

BACKGROUND: We investigated the role of gender on response to efavirenz (EFV)-containing regimens in previously antiretroviral-naive patients. METHODS: All previously antiretroviral-naive individuals from the Royal Free Hospital in London starting EFV from 1996 onward were included. Treatment failure was defined as the first of 2 consecutive viral load measurements >500 copies/mL more than 24 weeks after starting EFV. Standard survival methods were used to assess time to discontinuation and to treatment failure. RESULTS: Ninety-six women and 337 men were included. Women were mostly of black African ethnicity (64.6%) with a heterosexual risk (94.8%), whereas men were mostly white (66.8%; P < 0.0001) with a homosexual risk (71.2%; P < 0.0001). Women had lower CD4 counts when starting EFV (median [interquartile range [IQR] = 126 [36, 220] cells/mm for women vs. 190 [109, 268] cells/mm for men; P = 0.0003). After 48 and 96 weeks, 38.8% (95% confidence interval [CI]: 28.8% to 48.7%) and 56.3% (95% CI: 45.8% to 66.9%) of women had discontinued EFV compared with 28.3% (95% CI: 23.4% to 33.2%) and 41.8% (95% CI: 36.3% to 47.3%) of men (P = 0.005). The percentage experiencing failure by 48 and 96 weeks when ignoring treatment changes but censoring at the date of discontinuing all treatment was 1.3% (0.0%, 3.9%) and 4.4% (0.0%, 9.3%) for women compared with 3.8% (1.6%, 6.0%; P = 0.49) and 5.8% (3.0%, 8.6%) for men. Median (IQR) CD4 count increases at 48 weeks were +166 (+89, +239) cells/mm for women and +176 (+93, +263) cells/mm for men. CONCLUSIONS: Women seem to have comparable virologic and immunologic outcomes to first-line EFV-containing regimens compared with men, although they are more likely to discontinue the drug.

Success of clinical care for human immunodeficiency virus infection according to demographic group among sexually infected patients in a routine clinic population, 1999 to 2004.

BACKGROUND: The success of clinical care for human immunodeficiency virus infection may vary across demographic groups, because of patient- and health care-related factors. METHODS: A total of 2386 patients sexually infected with the human immunodeficiency virus were seen in a London clinic from July 1, 1999, to December 31, 2004. We examined demographic variation and trends over time in the prevalence of the following: (1) a CD4 cell count of 200/microL or less; (2) a viral load of greater than 50 copies/mL among patients receiving antiretroviral therapy (ART); and (3) a viral load of greater than 50 copies/mL among patients receiving ART for 24 weeks or longer. RESULTS: Subjects were homosexual men (63.1%), white heterosexual men (4.3%) and women (5.1%), and black African or other ethnicity heterosexual men (10.2%) and women (17.3%). The CD4 cell count at the first clinic visit was highest among homosexual men and lowest among black African heterosexual men. From 1999 to 2004, ART use increased from 61.9% to 75.5%. The prevalence of a CD4 cell count of 200/microL or less decreased from 19.6% to 9.0%. The prevalence of a viral load of greater than 50 copies/mL decreased from 36.9% to 14.5% among patients receiving ART, and from 31.2% to 10.1% among patients receiving ART for 24 weeks or longer. Demographic variation in the prevalence of each outcome was apparent among men throughout the period: homosexual men had the most favorable profile, and black African heterosexual men had the least favorable profile. Differences were much greater for low CD4 cell count than for raised viral load while receiving ART. There was no consistent demographic variation among women. Favorable trends over time occurred within each demographic group, and were as strong among black African patients as among other subgroups. CONCLUSIONS: The success of clinical care for human immunodeficiency virus infection increased substantially from 1999 to 2004 in this routine clinic population. All demographic subgroups benefited from improvements, despite ongoing differences in the prevalence of immunosuppression.

Factors influencing increases in CD4 cell counts of HIV-positive persons receiving long-term highly active antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy (HAART) results in an improvement in immunologic function. We sought to investigate the factors associated with increases in CD4 cell count among human immunodeficiency virus (HIV)-positive antiretroviral-naive patients starting HAART. METHODS: Five hundred ninety-six subjects were followed for a median of 2.5 years (interquartile range, 1.0-4.0 years). Factors associated with changes in CD4 cell counts in the first 3 months of HAART and from 3 months onwards were analyzed. RESULTS: After 6, 12, and 24 months of HAART, the median increases in CD4 cell counts were 114, 181, and 248 cells/mm3, respectively; 84%, 84%, and 80% of subjects had a virus load of <400 copies/mL during the same periods. White ethnicity, higher pre-HAART virus load, and lower pre-HAART CD4 and CD8 cell counts were associated with greater increases in CD4 cell counts during the first 3 months of HAART. From 3 months onward, a greater cumulative proportion of time spent with virus load <400 copies/mL was associated with a more favorable change in CD4 cell count (an average increase of 5.2 cells/mm3/year [95% confidence interval [CI], 3.8-6.7 cells/mm3/year] for each extra 10% cumulative time spent with a virus load <400 copies/mL) (P<.0001). For every 100 cells/mm3 higher in baseline CD4 cell count, the increase was 6 cells/mm3/year less (95% CI, 2-11 cells/mm3/year) (P=.02). Sex, risk group, age, and HAART regimen were not associated with increases in CD4 cell counts. CONCLUSIONS: These findings emphasize the importance of maintaining virological suppression and suggest other factors that influence long-term CD4 cell response.

Highly active antiretroviral therapy and cervical intraepithelial neoplasia.

Highly active antiretroviral therapy (HAART) has improved HIV prognosis, but its effect on cervical intraepithelial neoplasia (CIN), which is associated with HIV, is uncertain. Among 71 HAART-treated women the prevalence of CIN before HAART was 55%. After a median of 10 months after starting HAART the prevalence had increased to 62% (P = 0.20); 13% of patients experienced regression of a CIN lesion, and this was most strongly associated with a greater increase in CD4 cell count. Such studies will provide the basis for guidelines for monitoring CIN in HIV-positive women in the HAART era.