CROI 2023: Severe mpox outcomes with a low CD4 count and detectable viral load: a new AIDS-defining condition?
Most reports of mpox during the global outbreak in 2022 involved mild or moderate symptoms. However, people living with HIV were disproportionately affected, accounting for up to 50% of cases in some cohorts.
Additionally, many of the most severe outcomes, including those from the US, were in people with low CD4 counts, especially if not on ART. [1, 2]
A large international case series presented at CROI 2023 and published in the Lancet, reported on severe cases of mpox in people with advanced HIV, defined as CD4 <350 cells/mm3 or US CDC stage C. Of the 382 cases from 19 countries, 73% were from the US, Canada or Latin America, 27% from Europe and six cases were from Nigeria. They comprised 367 cisgender men, 4 cisgender women and 10 transgender women. [3, 4]
The median age was 35 (IQR: 30 to 43) years. At mpox diagnosis 349 (91%) were already diagnosed HIV positive, but only 228/349 (60%) were adherent on ART and only 193/382 (51%) had undetectable viral load <50 copies/mL. Viral load was 50 to 200, 200 to 1000 and >1000 copies/mL in 7%. 8% and 27% respectively. Overall, 33/382 (9%) were only diagnosed with HIV after presenting with mpox and 32/382 had at least one opportunistic infection.
Of note, 21 people (5%) had previously received an mpox prophylactic vaccination, although limited details were presented on this.
The median CD4 cell count was 211 (IQR: 117 to 291) cells/mm3 with 85/382 (22%) <100 cells/mm3 and 94 (25%) 100 to 200 cells/mm3.
A wide range of disseminated and local mpox complications were reported involving multiple organ sites, and these were significantly more serious in people with a CD4 count <100 compared to >300 cell/mm3. These complications included necrotising skin lesions (54% vs 7%), lung involvement (29% vs 0%), occasionally with nodules and secondary infections, and sepsis (44% vs 9%). Of the people with lung involvement, 8/11 had CD4 <100 cells/mm3.
Neurological complications were reported in 12/382 cases (3%), almost all with a CD4 count <100 cells/mm3. In 9/12 with altered mental state and confusion, 5/8 were due to sepsis.
Having a CD4 count <100 cells/mm3 was associated with a much higher number of skin lesions (median 30; IQR: 15 to 100) compared to the overall study. Although the median peak number of skin lesions was 15 (IQR: 8 to 35) in the overall cohort, this increased to 30 (IQR: 15 to 100) in those with a CD4 count <100 cells/mm3 and viral load >1,000 copies/mL, which included nearly all the 25 or so cases with 100 lesions and the 12 cases with >100 lesions. One person had >500 lesions.
The severity of many of the skin, mucosal and genital complications was often more marked than has been previously described.
Serious secondary bacterial infections were diagnosed in 76.282 cases (20%), median 15 (IQR: 8 to 35).
Overall, 107/382 (28%) of these cases were hospitalised and 27/382 (7%) died. All deaths were in people with a CD4 count <200 cells/mm3 (23/27 were <100 cells/mm3), and all had viral load >1,000 copies/mL.
Antiviral mpox treatment was not widely used, likely due to limited access in many countries. Tecovirimat (oral vs IV) was only used in 67/382 cases (52 vs 15 people respectively). IV immunoglobulin was used in a further 6 and cidofovir/brincidofovir in 7 cases. Resistance to tecovirimat was reported in the tiny number of cases (3/5) where this was tested for.
Management of the 85 people not on ART was complicated. IRIS was commonly reported – in 21/85 (25%) – as a consequence of starting/restarting ART and more than half these people died (12/21, 57%).
The authors discussed the very different and severe mpox outcomes in people with low CD4 counts off-ART and the high rates of IRIS (ART was started after about three weeks), as a very different phenomenon to the mpox-virus specific immune responses generated in people living with HIV on effective ART with CD4 counts >350 cells/mm3 and in people who are HIV negative.
The authors are already talking with international public health agencies on whether these data support adding mpox to the list of AIDS-defining conditions.
These results highlight a new clinical concern associated with very late HIV diagnosis and complications from loss-to-follow-up which are both still widely reported in many countries.
Many other studies at CROI 2023 reported that low CD4 count and detectable viral load were linked to more severe mpox outcomes. Also, importantly, that people at highest risk from mpox in the US were least likely to be able to access vaccines. [5, 6, 7, 8, 9, 10]
Guidelines on the clinical management of HIV should be urgently reviewed over the complications and to discuss whether the reports of IRIS-like responses support deferring ART for people diagnosed with advanced HIV and mpox coinfection.
This decision is difficult because the limited data report that mpox reduces CD4 counts in the first weeks of infection so the severe symptoms might be due to reduced CD4 counts, rather than a rapid increase in CD4s associated with IRIS. [11, 12]
A clear steer to start ART immediately in anyone not on treatment was recommended to US doctors in New York in a post-CROI briefing for how to manage severe mpox in people living with HIV. This excellent and timely webinar, available online, stressed that mpox will not resolve without an increased CD4 count from ART. 
Including mpox as an AIDS-defining infection in people with CD4 counts <350 cells/mm3 is important for highlighting the potential severity of these outcomes and to enable people to access appropriate supportive care.
Together, this shows the importance of effective mpox vaccination for gay and bisexual men who have sex with men and others at high risk.
Unless stated otherwise, references are to the Programme and Abstracts of the 30th Conference on Retroviruses and Opportunistic Infections, 19 – 22 February 2023, Seattle and hybrid. Some 2023 abstracts are available via the online CROI abstract database.
- Severe complication of monkeypox reported to the US CDC: risks associated with HIV and other causes of immunosuppression. HTB (3 October 2022).
- US CDC Health Advisory. Severe Manifestations of Monkeypox among People who are Immunocompromised Due to HIV or Other Conditions. (29 September 2022).
- Orkin C et al. Mpox in people living with HIV and CD4 counts <350 cells/mm3 – a global case series. CROI 2023, 19–22 February 2023, Seattle. Oral abstract 173.
- Mitja O et al. on behalf of SHARE-NET writing group. Mpox in people with advanced HIV infection: a global case series. Lancet Respiratory Medicine. (22 February 2023).
- Vaidya A et al. Characteristics and disparities among hospitalized persons with mpox in California. CROI 2023, 19–22 February 2023, Seattle. Poster abstract 902.
- Philpott DCE et al. CD4 count < 350 cells/mm3 increases risk of hospitalization with mpox in PWH. CROI 2023, 19–22 February 2023, Seattle. Poster abstract 903.
- Corma-Gómez A et al. Mpox virus infection is more severe in patients with uncontrolled HIV infection. CROI 2023, 19–22 February 2023, Seattle. Poster abstract 904.
- Silva MST et al. Impact of HIV infection on mpox-related hospitalizations in Brazil. CROI 2023, 19–22 February 2023, Seattle. Poster abstract 905.
- Garneau WM et al. Clinical outcomes among in- and outpatients with mpox in an urban health system. CROI 2023, 19–22 February 2023, Seattle. Poster abstract 907.
- Cholli PA et al. Characteristics of patients hospitalized with mpox during the 2022 us outbreak. CROI 2023, 19–22 February 2023, Seattle. Poster abstract 912.
- Agrati et al. Immunological signature in human cases of monkeypox infection in 2022 outbreak: an observational study. Lancet Infect Dis. 2022. (7 November 2023).
- Kennedy RB. Monkeypox infection creates immune signatures of disease progression. Lancet Inf Dis. 23(3):p265–266. (March 2023).
NYC Pandemic Response Institute. Navigating Challenges of Mpox (Monkeypox) for Treatment for People Living with HIV. Webinar 1 March 2023.
This report was first published on 21 February 2023. Comments were edited on 23 February.