Intersecting Pandemics of Epidemiology,Inequality,Genetics,and Immunology: COVID-19 and AIDS

Earlier this year, Winnie Byanyima, Under-Secretary-General of the United Nations and Executive Director of UNAIDS, gave a (virtual) presentation on activities of the Global Fund to Fight AIDS, Tuberculosis and Malaria. It was heartening to learn that, since its founding 21 years ago, new HIV infections have dropped by 54% and AIDS-related deaths have declined by 65%, a consequence of support, through the Global Fund and other organizations, of antiretroviral therapies (ART) for some 22 million people. ¹ Yet, the world did not meet 2020 HIV targets, ambitiously set by UNAIDS 5 years ago.

Complicating this failure, Secretary Byanyima noted that “Progress, already off track, is now under even greater strain as the COVID-19 crisis continues to rage, disrupting HIV prevention and testing services, schooling, violence prevention programmes and more.” ¹ In a 2020 Commentary for this journal, I reviewed data from the US, western Europe, and China indicating that people living with HIV (PLWH) appeared to be equally represented, perhaps even under-represented, among individuals with severe/critical COVID-19. ² This impression was confirmed by multiple reports examining several thousand cases of HIV/COVID-19 co-infections worldwide. ³ I was skeptical of the possibility that ART was responsible for this salutary outcome, even if in vitro experiments suggested susceptibility of SARS-CoV-2 to ritonavir-boosted lopinavir or tenofovir. Indeed, ART does not appear to protect against COVID-19 disease acquisition, progression, or death. ³ Multilevel determinants, including differences in access to quality healthcare and comorbidities for COVID-19 progression, appear to play a much more significant role than HIV-specific variables. Comorbidities important in clinical outcomes among PLWH, including older age, metabolic dysfunction, and pulmonary and hepatic disease, overlap substantially with those for COVID-19 progression. ^4,5

Subsequent articles in AIDS Patient Care and STDs examined specific COVID-19 vulnerable populations in the US and abroad. Migrant workers were highly impacted by national COVID-19 pandemic lockdowns and over-burdened health systems. ⁶ In the US, HIV diagnoses were known to decrease as the proportion of White residents increase across counties; COVID-19 diagnoses were then shown to follow a similar pattern. US counties with the highest proportion of White residents had the fewest cases of COVID-19, irrespective of geographic region or state political party representation. ⁷ A comprehensive analysis of data from the New York City public hospital system, for the period March 1, 2020 through April 2021, supported the conclusion that direct biological impacts of HIV do not negatively influence COVID-19–related outcomes when controlling for comorbidity and demographic variables. ⁸ Although the US Centers for Disease Control and Prevention (CDC) considers PLWH who have a low CD4 T cell count or who are not receiving HIV treatment to be at elevated risk for development of severe COVID-19, ⁹ it is also clear that systemic drivers—racism and racial segregation—place people of color at greater risk for COVID-19 and HIV, regardless of individual-level characteristics. ⁷

Genetics has some influence, predominantly based on gene flow from Neanderthals, but it is a double-edged sword. The major genetic risk factor for COVID-19 severity is found on chromosome 3 in a cluster encoding chemokine receptors. ¹⁰ These genes include CCR5, mutations of which protect individuals against acquisition of most strains of HIV. Hematopoietic stem cell donors selected for the homozygous Δ32CCR5 mutation were the basis for all three documented HIV cures following bone marrow transplantation, including the Berlin patient, Timothy Brown, the London patient, Adam Castillejo, and, very recently, a multi-racial woman treated at my institution. ¹¹ The chromosome 3 COVID-19 risk allele, while contributing to COVID-19 progression, offers a 27% reduction in risk for HIV infection. ¹⁰ It arose in frequency some 20,000–10,000 years ago, predating the HIV pandemic, and is therefore unlikely to have arisen in response to that virus. What did account for its selection and maintenance is open to speculation; smallpox, Yersina pestis (the Black Plague), and cholera are suggested candidates. ¹⁰ In terms of differentially influencing populations, Neanderthal haplotypes are rare or absent in Africans, ¹² so while the presence of the chromosome 3 variant contributes to the severity of SARS-CoV-2 infection among Caucasians, but not those of African ancestry, it offered considerable protection against HIV to the former.

This information is interesting, and may offer future therapeutic insights. However, what is critical now, in the context of a dual pandemic, is recognition that health injustice, not biologic imperatives, needs to be mitigated. As Secretary Byanyima stated, “We know that HIV infection makes a person much more likely to die of COVID-19. We also know that sub-Saharan Africa is home to two thirds of people living with HIV. But just over 12% of people in Africa have received two doses of a COVID-19 vaccine.” ¹ The Global Fund strategy for the next 5 years asserts: “End Inequalities. End AIDS.” An identical message pertains to COVID-19.

First, Secretary Byanyima highlighted the need to vastly expand COVID-19 vaccine availability and distribution in Africa and other resource-poor regions. This will be complex. Recent data for currently available mRNA or adenovirus-based vaccines indicate the necessity for booster doses, particularly among PLWH. Vaccine efficacy is lower among the immune suppressed, including individuals infected with HIV. PLWH with CD4+ T cell counts <500 cells/μl, and notably <200 cells/μl, have significantly lower anti-SARS-CoV-2 antibody titers compared with PLWH with CD4 counts >500 cells/μl following a standard vaccination protocol without boosters. ¹³ This is an important distinction as in a recent US study, 28% of those newly diagnosed with HIV had CD4 cell counts <200/μl. ¹³ What is encouraging is that, compared to fully vaccinated patients without booster receipt, patients with booster had an 83% reduced risk of COVID-19–related death, independent of demographics, geographic region, comorbidities, or HIV status. ¹⁴ Global vaccination, with a particular focus on PLWH, must be a priority. One recent case from sub-Saharan Africa illustrates why.

Scientists recently mapped the antibody neutralization characteristics of a SARS-CoV-2 strain that evolved over 6 months from ancestral virus in a person with advanced HIV disease in South Africa. ¹⁵ The individual had been infected prior to emergence of the Beta and Delta variants. This new isolate harbored a myriad of mutations found in Omicron, the latest iteration of CoV-2. Its evolution is consistent with the hypothesis that SARS-CoV-2, replicating in immunocompromised hosts, such as those with untreated HIV infection, may escape vaccine-based immunity. The driving force behind evolution of this highly mutated variant may have been the presence of very low levels of anti-SARS-CoV-2 antibodies that could select for antibody escape mutations in the absence of the capacity to clear those viruses, and might also, through the well-documented phenomenon of antibody-dependent enhancement (ADE), ¹⁶ facilitate that infection.

Vaccine hesitancy does not appear to be a major issue for PLWH in the US, but it's of growing global concern. Data from a national sample of 496 PLWH collected between March and May 2021 found 64% of participants had received at least one dose of a COVID-19 vaccine, ¹⁷ a rate similar to the 63.5% of PLWH in New York State who had completed such vaccinations. ⁹ However, that coverage was significantly lower than for the general adult population in New York State, at 75.0%. ⁹ Vaccine uptake among PLWH was associated with older age, more years living with HIV, higher educational attainment, male sex, persons identifying as nonbinary or nonconforming, and non-Hispanic White. ^9,17 Globally, different issues may be paramount. The US has delivered some 300 million COVID-19 vaccine doses to more than 100 countries, but many more doses are required, and vaccine hesitancy is one of the biggest challenges. ¹⁸ “Vaccine hesitancy and access go hand in hand,” according to Dr. Amanda Cohn of the CDC. ¹⁸ “We have to make sure vaccines are highly accessible so that it's easy for individuals to make the choice to get vaccinated. … With polio vaccines, we went into people's homes and into those communities and villages across the world. It took extraordinary efforts to get that done. One of the key ways to increase vaccine demand is to normalize it in communities. If we think that every community in this country has its own perspective and challenges, that's just times a million across the world.”

Second, easing a transition to telehealth and expansion of mobile health devices, important in facilitating access to HIV testing and ART adherence in both resource-rich and resource-poor settings, ^19,20 will be necessary. Technical barriers, unfamiliarity and patient distrust, and consideration of culturally significant absence of human contact and connection will need to be addressed. ²⁰

Regardless of the technologies involved, it is certain that, as stated in a recent article by CDC directors directly involved in tackling both HIV and COVID-19, “A global pandemic must be met with global solutions.” ²¹