Last reviewed: March 11, 2022
The RTLN editors acknowledge special contributions and review by Rachel Bender Ignacio, MD, MPH and Adrienne E. Shapiro, MD, PhD.
Current recommendations for COVID-19 management, diagnostic evaluation and infection prevention for people with HIV do not differ from those of the general population. PWH, however, frequently face adverse social determinants of health and structural factors that may lead to higher SARS-CoV-2 exposure and infection (Price-Haywood, June 2020; Nydegger, June 2020; Millett, October 2020). Additionally, medical comorbidities associated with poorer COVID-19 outcomes are common in the aging population of PWH (Dandachi, September 2020; Palella, December 2019) and the clinical care cascade for PWH may be severely disrupted by pandemic measures. Taken together, emerging evidence suggests that severe COVID-19 outcomes may be more common in PWH, particularly in subpopulations with multimorbidity and/or low CD4 T-cell count (Western Cape Department of Health, October 2021; WHO, July 2021; Durstenfeld, March 2022; Yang, October 2021). Vaccination is a promising mode to reduce COVID-19 morbidity in PWH, with small sub-studies of vaccine trials and observational data supporting good safety and immunogenicity among people on antiretroviral therapy with preserved CD4 count.
There are limited data as to whether susceptibility to SARS-COV-2 infection and COVID-19 incidence is higher among PWH after controlling for testing rates, medical comorbidities and structural factors such as racial/ethnic identity or socioeconomic status. Additionally, it is not yet known if lower CD4 count or unsuppressed HIV viral load are associated with increased risk of SARS-CoV-2 infection, per se. Data from a large health care system during the first U.S. COVID-19 wave did note a two-fold higher incidence of SARS-CoV-2 diagnoses among PWH despite their being younger and with fewer comorbidities than people without HIV in the care network (Chang, September 2021). A contemporaneous series from New York state, however, did not detect a difference among PWH in the standardized rate of having a positive COVID-19 test (Tesoriero, February 2021). Notably, cross-sectional spatial analyses in the U.S. have shown clustering and correlation of incident COVID-19 diagnoses in regions with higher new HIV diagnosis rates, which might reflect local population public health measures (Luan, October 2021).
HIV infection, especially in those with unsuppressed HIV viral load and low CD4 count (<200 cells/μL), is a well-established risk factor for opportunistic viral infections, including respiratory viruses (Sellers, March 2020). Due to a clear increased risk of severe COVID-19 in people with cancer, solid organ transplant and other immunocompromising conditions, there is concern that the immune dysregulation associated with HIV will predispose to more serious COVID-19 outcomes. This may compound the impact of prevalent non-HIV medical factors in this population that are known to be associated with severe COVID-19.
Several population-based studies have assessed comparative COVID-19 outcomes in PWH, albeit with varying degrees of adjustment for both non-HIV comorbidity and HIV-associated immune compromise. A large global WHO analysis of hospitalized patients with COVID-19 found a modest increase in severe/critical illness (aOR, 1.13) in PWH, including a 30% increased risk of death as compared to those without HIV, although no stratification on CD4 or viral load was available (WHO, July 2021). Several early population and health system-based studies in the U.S. and South Africa also found HIV status was associated with a two-fold overall increased risk of death (Tesoriero, February 2021; Western Cape Department of Health, October 2021). These series, however, encompassed distinct populations with respect to HIV control and opportunistic coinfection (e.g., tuberculosis), in addition to variable adjustment for comorbidity. The U.S. N3C platform studied >1.4 million cases of COVID-19, including in >13,000 PWH, and found a 20%-30% higher risk of hospitalization and death associated with HIV status after rigorous adjustment for non-HIV demographic and medical factors (Yang, November 2021). Within the PWH group, CD4 <200 (3-4x higher) and to a lesser extent unsuppressed HIV viral load (1.5x higher) were associated with COVID-19 hospitalization and mortality versus PWH with less immune dysfunction. Furthermore, a U.S. CFAR cohort of PWH confirmed a strong association of classical non-HIV comorbidities (e.g., diabetes, obesity, kidney disease) with worse COVID-19 outcomes, as well as the independent association of CD4 count <350, lower CD4 nadir (<200) and lower CD4/CD8 ratio with hospitalization (Shapiro, April 2022).
Taken together, as has been found in other immunocompromised populations, there is a strong impact of non-HIV comorbidities such as age, metabolic syndrome and end-organ disease on COVID-19 outcomes in PWH. Additionally, lower CD4 count (<200-350) is associated with severe disease and identifies a subpopulation at greater risk for COVID-19 morbidity and mortality. The association of unsuppressed HIV viral load with severe COVID-19, although suspected, is less clear, likely related to the high prevalence of ART use in studied populations to date.
IDSA and NIH guidelines currently recommend against the use of lopinavir/ritonavir (LPV/r) for treatment of patients with COVID-19.
In the pandemic’s early stages, it was hypothesized that protease inhibitors, specifically LPV/r, may have activity against SARS-CoV-2. This was primarily driven by in vitro antiviral activity of high-dose LPV/r against MERS-CoV and SARS-CoV-1 (Yao, February 2020) as well as supportive animal and observational human data from earlier coronavirus outbreaks (Chan, December 2003; Chu, March 2004; Chan, December 2015). This led to wide use of LPV/r until several large randomized controlled trials confirmed a lack of benefit (Cao, May 2020; RECOVERY Collaborative Group, October 2020; WHO SOLIDARITY, July 2021).
Other observational studies indicated use of nucleoside reverse transcription inhibitors, specifically tenofovir disoproxil (TDF) or tenofovir alafenamide (TAF), may be associated with lower risk of acquiring SARS-CoV-2 and severe COVID-19 outcomes (Del Amo, June 2020; Boulle, August 2020). However, these studies were limited by significant confounding, including that the use of TDF might be restricted to less frail people such as those with preserved kidney function. Subsequent observational studies have not found a relationship between TDF/TAF and risk of SARS-CoV-2 acquisition or severe outcomes (Vizcarra, May 2020; Ho, June 2020; Charre, October 2020). Several clinical trials are investigating the use of TDF or TAF for treatment or prevention of COVID-19. One small trial in healthy people without HIV found a moderate reduction in SARS-CoV-2 cycle threshold during early TDF treatment, albeit without impact on clinical outcomes and accompanied by frequent gastrointestinal adverse events (Parienti, June 2021).
At this time there is no evidence to suggest that any particular antiretroviral agent improves or worsens COVID-19 outcomes in PWH. Thus, guidance recommends standard approaches to initiation and continuation of ART with a focus on reducing HIV-associated immune compromise and achievement of virologic suppression (HIV Medicine Association).
The seminal trials of COVID-19 vaccine safety and immunogenicity included small subgroups of PWH (<2,000 total people), all of whom had preserved CD4 counts (>300) and viral load suppression on ART. Therefore, most efficacy data are inferred from the general population. PWH-specific trials data were published for the ChAdOx-1 (AstraZeneca) adenoviral vaccine, indicating similar humoral and cellular immunogenicity in 157 PWH, without safety concerns (Frater, June 2021). It was noted, however, in the Novavax phase 3 trial in South Africa that vaccine effectiveness increased from 50% to 57% versus the B.1.351 variant when 201 PWH were excluded from analysis (Shinde, May 2021). The Janssen vaccine study included the largest group of PWH (n=1,218), yet only six total COVID-19 cases were reported (two in the vaccine arm, four in the placebo arm), limiting inference.
Several subsequent observational studies of mRNA vaccines have supported good immunogenicity and tolerability in PWH with preserved CD4 count on ART (Woldemeskel, July 2021; Ruddy, November 2021). Two comparative studies, however, have indicated lower humoral vaccine immune responses in PWH, particularly among those with lower CD4 counts. In one series of Pfizer BNT162b2 recipients, PWH with excellent viral control on ART showed similar rates of seroconversion but modestly lower antibody and neutralizing activity versus non-HIV controls (Levy, December 2021). Another study of mRNA vaccinees found a 2.4-fold higher incidence of humoral nonresponse (IgG and surrogate neutralization levels) in PWH versus matched people without HIV, notable for a continuous negative association with decreasing CD4 count (Spinelli, December 2021). Unsuppressed viral load (>200 copies) was also associated with poorer humoral response as well as receipt of the Pfizer/BNT162b2 vaccine (vs. Moderna mRNA-1273).
Importantly, there may be higher rates of infection after primary vaccination (i.e., “breakthrough”) among PWH versus people without HIV. One population-level analysis among people with immunocompromise indicated a 33% higher incidence rate of breakthrough among PWH, albeit without accounting for HIV-specific factors (Sun, December 2021). Additionally, a large NA-ACCORD matched cohort study of >30,000 PWH, primarily mRNA-vaccinated with good HIV control, found a 44% higher hazard of breakthrough without a clear association with viral load or CD4 count (Coburn, December 2021 - preprint, not peer-reviewed).
Taken together, these findings support the recommendation that PWH with preserved CD4 count and viral control on ART should follow the same vaccination schedule and recommendations as in the general population without HIV. In contrast, PWH with suppressed CD4 count, high viral loads and/or AIDS should follow recommendations for moderately-to-severely immunocompromised populations that recommend a third primary series vaccine dose before booster vaccination. All available vaccines in the U.S. are non-live and thus are recommended for PWH irrespective of CD4 count.