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People with HIV in England had double the risk of dying compared to the rest of the population during the first wave of the COVID-19 pandemic up to 16 June 2020, Dr Sara Croxford of Public Health England reported at the joint British HIV Association and British Association of Sexual Health and HIV conference today.

The findings are similar to those of two large studies published in 2020, which also found a raised risk of death from COVID-19 in people with HIV in the United Kingdom.

The Public Health England study found that over two-thirds of COVID-19 deaths in people living with HIV were in Black, Asian or other non-White ethnic groups.

A second study, looking at COVID-19 cases reported to HIV clinics in the UK in the second wave of the pandemic, found that Black Africans had a higher risk of severe illness, as did people who were obese. The study also found that people with CD4 counts below 200 had a higher risk of severe illness compared to people with higher CD4 counts.

Public Health England: risk factors for COVID-19 death
The Public Health England study used HIV surveillance data, which stores anonymised information on people by first initial, date of birth, gender and neighbourhood, and matched these data with reported deaths from COVID-19 to identify all adults with HIV who died from COVID-19 between 2 March and 16 June 2020, the first wave of the pandemic in England.

The researchers identified 99 deaths from COVID-19 in people living with HIV. Detailed clinical records were available in 94 cases. This represents approximately 0.1% of the population of people with HIV in England, showing that overall COVID-19 mortality remained low in people with HIV.

Find out more in our About HIV pages
Croxford compared crude mortality rates from COVID-19 in people living with HIV and the rest of the population, finding the highest levels of mortality in Black people with HIV over 60 (985 deaths per 100,000), Asian people with HIV over 60 (781 per 100,000), people living with HIV in London aged 60 or over (722 deaths per 100,000) and people with HIV over 60 living in the most deprived areas (538 deaths per 100,000).

Crude mortality rates were lower in people without HIV aged over 60 in London (521 per 100,000), Black over-60s (751 per 100,000) and Asian over-60s (460 per 100,000) but in most other respects, differences in mortality were less pronounced.

Looking at the entire population, including people with HIV, four factors increased the risk of dying from COVID-19:

Gender: women were 45% less likely to die from COVID-19 compared to men (adjusted risk ratio 0.55, 95% CI 0.51-0.69, p < 0.001).
Age: each 5-year increase in age raised the risk of death by 79% (aRR 1.79, 95% CI 1.77-1.81, p < 0.001).
Ethnicity: Black people were at more than three times greater risk of dying from COVID-19 (aRR 3.44, 95% CI 3.06-3.87, p < 0.001), Asian people at more than twice the risk (aRR 2.24, 95% CI 2.00-2.52, p < 0.001) and other ethnicities at more than three times the risk compared to White people (aRR 3.23, 95% CI 2.86-3.65, p < 0.001).
HIV status: people living with HIV were approximately twice as likely to die from COVID-19 as people without HIV (aRR 2.18, 95% CI 1.76-2.70, p < 0.001).
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Among people with HIV who died of COVID-19, 53% were aged 60 or over. Sixty-eight per cent were Black, Asian or another minority ethnic group, whereas 35% of people living with HIV in England are Black, Asian or another minority ethnicity.

Over half (58%) had a CD4 count below 350 at the time of death, 94% were on HIV treatment at the time of death and 91% had a last viral load result below 200.

Eighty-seven per cent of people with HIV who died had at least one underlying condition that increased the risk of a severe COVID-19 outcome, most commonly cardiovascular disease (69%), obesity (49%), type 2 diabetes (48%), chronic kidney disease (41%) or high blood pressure (39%). The study was not able to compare the prevalence of underlying conditions between people with HIV and the rest of the population, so it is not possible to say whether people with HIV had a higher number of underlying conditions than people without HIV, which might explain the increased risk of death.

British HIV Association registry of COVID-19 cases in people living with HIV
More news from BHIVA & BASHH 2021
The British HIV Association (BHIVA) carried out a registry study of COVID-19 cases in people attending HIV clinics in the United Kingdom, to identify factors associated with severe outcomes. The study collected data between October 2020 and March 2021, the second wave of the pandemic in the United Kingdom.

As this study depends on clinics to submit data, and on the quality of data collected by clinics, this study cannot calculate what proportion of people living with HIV contracted SARS-CoV-2 or experienced COVID-19 symptoms. Furthermore, cases were included on the basis of either a positive COVID-19 test or symptoms that were suggestive of COVID-19. People who had the infection without symptoms and people with infections that did not lead to hospital admission are likely to be under-represented in this study, potentially leading to an overestimate of the risk of severe illness.

Find out more: COVID-19 and coronavirus in people living with HIV
Clinics reported 1310 cases and supplied a standardised dataset of demographic, clinical and lifestyle information and HIV-related data including most recent CD4 and viral load. They also reported COVID-related clinical information including potential exposure risks, testing, symptoms, hospitalisation and severity of presentation.

The study looked for factors associated with two outcomes: severe illness requiring oxygen or invasive ventilation, and poor outcome (either death, or continued hospitalisation or symptoms lasting more than three months).

The 1310 cases were predominantly male (62%) and half were aged 50 or over. Thirty-eight per cent were Black African, 56% were born outside the UK or had an unknown country of birth, 34% had an occupational risk for COVID-19 exposure and 16% had close contact with a confirmed COVID-19 case.

Of the reported cases, 78% had symptoms, most commonly fever (47%), cough (51%), shortness of breath (36%) and loss of sense of smell (23%). Fifty-nine per cent of these symptomatic cases had been confirmed by a positive test result. Just under 10% of cases reported were asymptomatic, of which 95% were confirmed by testing.

Looking at the HIV-related characteristics of the reported cases, just under 5% had a CD4 count below 200. Four per cent had an AIDS-defining illness at the time they were diagnosed with COVID-19.

"The findings reinforce the importance of advice for prompt vaccination against COVID-19 for people with low CD4 counts and/or recent AIDS-defining illness."

Although the median lowest-ever CD4 count was 257, the median current CD4 count was 611. Just under 15% of the sample were judged to be at risk of having recently had a detectable viral load, either because they were not on antiretroviral treatment, had been diagnosed in 2019 or 2020, or had had a confirmed detectable viral load since January 2019.

As for underlying conditions, reported cases had a median of one underlying condition known to increase the risk of severe COVID-19, most commonly high blood pressure (24%), obesity (19%) or raised lipid levels (17%). Thirteen per cent were current smokers. The median body mass index was 28 (IQR 24.5-32.3), placing the majority of the reported cases in the ‘overweight’ or ‘obese’ weight categories.

Twenty-three per cent of cases were admitted to hospital and 18% of the entire caseload had severe COVID-19 presentation that required oxygen support or mechanical ventilation. A severe illness was almost four times more likely in Black African people (odds ratio 3.90, 95% CI 2.46-6.17, p = 0.0001) compared to White people.

Similarly, people who were obese (body mass index of 30 or above) were almost four times more likely to suffer severe illness (OR 3.95, 95% CI 1.87-8.38). Each underlying condition associated with increased COVID-19 risk in the general population increased the risk of severe illness in people with HIV by 24% (OR 1.24, 95% CI 1.14-1.36, p = 0.0001). A current AIDS-defining illness also increased the risk of severe illness (OR 3.32 (95% CI 1.61-6.82, p = 0.005).

Glossary
detectable viral load
AIDS defining condition
high blood pressure
symptomatic
body mass index (BMI)
Women were at lower risk of severe illness than men (OR 0.46, 95% CI 0.30-0.71, p = 0.0004), and people with CD4 counts above 200 were at lower risk than people with CD4 counts below this level. There was no difference in the risk of severe illness between people with CD4 counts in the 200-350 range and those with CD4 counts above 350 (OR 0.40 and 0.50 respectively, p = 0.02).

Fourteen per cent had a poor outcome (either death or still hospitalised or symptomatic three months after presentation). After controlling for severe illness at the time of presentation, poor outcome was associated with shortness of breath (OR 2.36, 95% CI 1.44-3.87, p = 0.0006), underlying conditions (OR 1.17, 95% CI 1.05-1.30 for each condition, p = 0.006) and severe illness (OR 8.47, 95% CI 4.87-14.73, p = 0.0001). Age and CD4 count did not affect the risk of a poor outcome.

The BHIVA group conclude that the findings reinforce the importance of advice for prompt vaccination against COVID-19 for people with low CD4 counts and/or recent AIDS-defining illness.

References
Sabin C et al. Coronavirus (COVID)-19 in people with HIV in the UK: Initial findings from the BHIVA COVID-19 Registry. Fifth Joint Conference of the British HIV Association (BHIVA) and the British Association for Sexual Health and HIV (BASSH), abstract 08, 2021.

Croxford S et al. COVID-19 mortality among people with HIV compared to the general population during the first wave of the epidemic in England. Fifth Joint Conference of the British HIV Association (BHIVA) and the British Association for Sexual Health and HIV (BASSH), abstract 09, 2021.

Islatravir (MK-8591) is an antiretroviral drug with a novel mode of operation that has excited a lot of interest in the last two years because of its extraordinary persistence in the body. This means it may only need to be given once a week as an HIV treatment, and a subcutaneous implant that releases the drug might only need to be replaced once a year when used as pre-exposure prophylaxis (PrEP).

Pending the results from studies of an implant, however, a study presented at the HIV Research for Prevention (HIVR4P) virtual conference yesterday showed that islatravir as PrEP can be given very easily as a pill that only needs to be taken once a month.

Professor Sharon Hillier of Pittsburgh University presented the results of a US-based phase IIa study whose aim was to establish the level and persistence of islatravir in the blood and tissues of 250 volunteers aged 18-65 who were at low risk of HIV infection. Drug-level data in blood plasma is available for 192 people up to the end of October, which was the most recent date of analysis.

Glossary
plasma
phase II
phase I
oral
implant
The volunteers were divided into three groups: 100 volunteers each received six oral monthly doses of either 60mg or 120mg tablets of islatravir, while 50 received a placebo. After the sixth dose, drug levels will continue to be measured for another three months while participants and researchers are still ‘blinded’, i.e. do not know which study arm they are in, and then for a further five months unblinded.

Based on single-dose phase I studies, drug levels over each month and their range were forecast to stay well above the level of 0.05 picomols of drug per million cells which is the threshold of efficacy. The purpose of the phase 2 study was to see how closely actual drug levels fitted this model.

The 192 people whose results were presented had an average age of 32, and two-thirds of them were women. Nearly two-thirds (64%) were White, of whom one in six were of Latino origin, while 30% were Black; only a few were mixed-race or of other ethnicities.

Find out more in our About HIV pages
Islatravir is not completely without side effects, and more than half (53%) reported at least one adverse event, which may or may not have been connected to the drug. The most common ones reported were gastrointestinal symptoms (nausea, stomach pain, diarrhoea) and headache. Two discontinued the drug due to adverse events, one due to a rash, and four had transient rises in their liver enzymes. However, no adverse events were classed as serious. Six others discontinued the trial early for reasons not related to side effects.

"The once-monthly dose provides enough forgiveness for people to be a couple of weeks late in taking their next dose.”

The key data reported to HIVR4P were drug levels reported immediately after dosing and then each week during the first and sixth month of the trial. For the months in between, just the trough levels (i.e. the ones immediately before taking the next dose) were measured.

The trough levels each month were in the order of one picomol per million cells in volunteers taking the 60mg dose (in other words, 20 times the estimated efficacy threshold) and in the order of 40-50 times the efficacy threshold in those taking the 120mg dose. All levels fell within the pre-modelled range and indeed the range between different volunteers was considerably narrower than forecast, with only a two- to threefold range between the lowest and highest levels at any time point. Levels neither increased nor decreased over the six months, with the peak and trough levels remarkably consistent.

In a minority of volunteers, data was available for drug levels up to 28 weeks, which is eight weeks after the last dose. These levels were still four to five times the estimated efficacy threshold. Hillier said that this showed that the once-monthly dose “provides enough forgiveness for people to be a couple of weeks late in taking their next dose.”

A subgroup of 54 participants had biopsies taken to measure drug levels in re**al and vaginal tissues and also intracellular levels, but these results are not yet available. The phase I studies suggest that these are not likely to be substantially different to plasma levels.

In terms of efficacy against HIV, so far the only data come from monkeys, who were completely protected from viral challenge by monthly islatravir.

More news from HIVR4P 2021
However, human efficacy studies are imminent. The IMPOWER 022 study will recruit 4500 cisgender women in the US and in sub-Saharan Africa, and the IMPOWER 024 study will recruit 2000 gay and bis*xual men and transgender women in a number of different countries. Both will compare the efficacy of monthly islatravir against daily tenofovir disoproxil fumarate (TDF)/emtricitabine or, in the case of IMPOWER 024, either TDF or tenofovir alafenamide (TAF) plus emtricitabine. The enrolment of US participants in IMPOWER 022 will start next month, African participants a few months after that, and IMPOWER 024 will start enrolling in late summer this year.

The dose tested will be 60mg because it was felt that 120mg was not likely to provide significantly greater efficacy to be worth risking more frequent side effects.

In terms of how monthly oral islatravir PrEP will eventually be provided (assuming it’s effective), Hillier said “We envisage people could go to a pharmacy once a month and either take it right there or take it home with them. This would be ideal for people who don’t want an injection but also don’t want to risk the discovery of a bottle of pills.”

References
Hillier S et al. Trial design, enrolment status, demographics, and pharmacokinetics (PK) data from a blinded interim analysis from a phase 2a trial of Islatravir once monthly (QM) for HIV pre-exposure prophylaxis (PrEP). HIV Research for Prevention (HIVR4P) virtual conference, abstract OA04.05, 2021.

View the abstract on the conference website.