Mpox (formerly known as monkeypox) can be much more severe in people living with HIV who have a very low CD4 count – so much so that some experts are calling for it to be classified as an AIDS-defining opportunistic infection. The findings come from a global case series presented Tuesday at the 30th Conference on Retroviruses and Opportunistic Infections (CROI 2023) in Seattle and published simultaneously in The Lancet.
The series included nearly 400 cases of mpox among HIV-positive people with a CD4 T-cell count below 350. Many patients had severe necrotising lesions resulting in tissue death, some people’s lungs were affected and others had sepsis. The overall mortality rate was 7%, but it rose to 27% among those with a CD4 count below 100. These findings are “distressing,” Professor Chloe Orkin of Queen Mary University of London told the conference. Outcomes were “very starkly different” for those with the lowest CD4 levels.
The silver lining is that no one with well-controlled HIV and no one who received an mpox vaccine died, which suggests that starting and staying on antiretroviral therapy can prevent severe outcomes. However, Orkin added a note of caution, advising clinicians who care for untreated patients with severe mpox to be alert for immune reconstitution inflammatory syndrome, or IRIS, a worsening of symptoms that can occur when people start antiretrovirals with a very low CD4 count.
Mpox and HIV
As aidsmap previously reported, the UK Health Security Agency (UKHSA) reported the first cases in an mpox outbreak outside Africa in May 2022. As of 19 December, UKHSA had identified 3730 cases in the UK. Worldwide, there have been more than 86,000 cases in 110 countries, resulting in 96 deaths, according to the World Health Organization. Most cases have been among gay, bisexual and other men who have sex with men.
Mpox cases have declined dramatically since the outbreak peaked in late summer, but all is not well: cases may be underreported, mpox vaccination rates are low, and vaccines and antiviral treatment for mpox remain unavailable in many countries.
In particular, mpox remains a risk for people living with HIV, who account for up to half of all cases in the 2022 outbreak. Several studies have shown that HIV-positive people on antiretroviral therapy with an undetectable viral load and an adequate CD4 count do not fare worse than HIV-negative individuals. But that’s not the case for those with more advanced HIV.
To characterise the global mpox outbreak, Orkin and a large team of colleagues formed an international collaboration known as the SHARE-net Clinical Group. The group has already published studies describing the spectrum of mpox symptoms and mpox cases among women.
The new case series compiles data from 382 HIV-positive people with mpox in 19 countries. A third had a CD4 count between 200 and 300, a quarter between 100 and 200 and 22% below 100. (200 is the threshold for an AIDS diagnosis.) About a quarter of the case reports came from Europe, nearly three-quarters from the Americas and less than 2% from Africa. Most were cisgender men, four were cisgender women and 10 were transgender women. The median age was 35 years. Although about 90% were previously diagnosed with HIV, just 60% were on antiretroviral treatment and only half had an undetectable viral load. What’s more, only 7% had received an mpox vaccine.
Mpox looked like a very different disease among people with uncontrolled HIV, according to Orkin. “When I saw the fatality rate, I felt horrified,” she said. “If there’s someone in your life who hasn’t had an HIV test and may have low CD4 count without knowing it, if they get mpox it could have catastrophic outcomes.”
Most people developed a skin rash, with the number, size and extent of the lesions increasing as CD4 counts fell. Nearly a quarter developed large necrotising lesions, which in some cases coalesced, or merged. Many had disseminated lesions far from the site of viral entry, suggesting systemic infection carried through the bloodstream. Lesions were “teeming with virus,” Orkin said, indicating that people with immunosuppression are unable to contain the infection.
Some patients experienced more severe complications, including inflamed tonsils, swollen lymph nodes that impeded swallowing or breathing, necrotic genital lesions, urinary obstruction or bowel perforation.
Internal organs were also affected. About 9% overall – but 29% of those with a CD4 count below 100 – developed respiratory complications, including lung nodules, 5% had eye complications and 3% had neurological manifestations. Nearly a quarter developed secondary bacterial infections. All types of complications were much more common among those with the lowest CD4 counts.
Nearly 30% of the patients were hospitalised, including 9% who required intensive care. However, just 16% were treated with the antiviral drug tecovirimat (TPOXX), which was only available to people in Europe and the US and two people in Brazil. Some people progressed and died despite repeated courses of tecovirimat.
Overall, 27 people (7%) died. But mortality was heavily concentrated among those with the most advanced immune suppression. Most of those who died had multiple severe mpox complications and their median CD4 count was only 35.
No one with a CD4 count above 200 died. In contrast, 15% of people with a count below 200 and 27% of those with a level below 100 died. HIV viral load also played a role: among those with a CD4 level below 100, the mortality rate was 7% for those with viral suppression versus 30% for those with a high viral load.
Eight-five people either started antiretroviral treatment for the first time or restarted therapy. Of these, 25% had suspected IRIS. Among those with IRIS, 57% died. In people with a very low CD4 count, the immune system doesn’t notice the virus, Orkin explained, but when it “wakes up” after starting antiretrovirals, it can trigger severe inflammation.
With some opportunistic illness, such as meningitis, it’s important to get the existing disease under control before starting antiretroviral therapy. This may also be the case for mpox. The people who developed IRIS in this study started antiretrovirals a median of 21 days after presenting with mpox symptoms. It is unknown whether starting HIV treatment earlier, when mpox symptoms first appear, would lead to better outcomes.
The difference in outcomes between people with well-controlled and uncontrolled HIV clearly show the “huge advantage” of being on antiretroviral therapy, Orkin said. “Late HIV treatment may be the main reason things were so bad.” However, she added, “sometimes in very sick people, the timing of HIV treatment has to be carefully considered.”
Orkin and colleagues argue that mpox acts as an opportunistic infection in people with uncontrolled HIV and the severe necrotising form is an AIDS-defining illness. They called on the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) to add mpox to the 14 other opportunistic conditions in international disease classifications. In some countries, Orkin noted, having an AIDS diagnosis can unlock certain services and financial support.
The findings paint a disturbing picture of inadequate health care for people living with HIV worldwide. Many of those in the study did know their HIV status, had not been vaccinated against mpox and did not receive the antiviral tecovirimat. The study authors advised that clinicians should be alert for mpox progression in people known to have HIV, and that all people with mpox should be tested for HIV if their status is unknown.
The study authors also urged that HIV-positive people with CD4 counts below 200 should be prioritised for mpox antivirals and vaccines – including in those countries where these resources are not currently available. Orkin added that people with HIV should receive two doses of the vaccine using the subcutaneous rather than the dose-sparing intradermal administration method.
Dr Meg Doherty, head of WHO’s global HIV, hepatitis and sexually transmitted infection programmes, said the agency will review the data with international experts and consider the researchers’ recommendations. “The recent case series makes a very compelling case that in people living with HIV and with a CD4 count less than 200, the risk of severe disease and death from mpox is high and disseminated infection behaves like other opportunistic infections,” she said in a statement. “This emphasizes the need for offering HIV testing for those with mpox and for people living with HIV to access early treatment, mpox vaccines and antivirals in case of infection.”
Mitja O et al (Orkin C presenting). Mpox in people living with HIV and CD4 counts < 350 cells/mm3: a global case series. 30th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 173, 2023.
Mitja O et al. Mpox in people with advanced HIV infection: a global case series. Lancet, 21 February 2023. DOI: 10.1016/S0140-6736(23)00273-8