SARS-CoV-2 seropositivity and risk factors in African women living with HIV and their Infants

doi:10.21203/rs.3.rs-3423146/v1

Background

SARS-CoV-2 seropositivity data in women living with HIV (WLHIV), their infants and associated factors in this subpopulation remain limited. We retrospectively measured SARS-CoV-2 seropositivity from 07/2020-11/2021 among WLHIV and their children in the PROMOTE observational cohort in Uganda, Malawi, and Zimbabwe prior to widespread SARS-CoV-2 vaccination in those countries.

Methods

Sociodemographic, clinical data and blood were collected every 6 months. Plasma stored during 3 waves of the COVID-19 pandemic in East/Southern Africa were tested for SARS-CoV-2 specific IgG antibodies (Ab) using serological assays that detect adaptive immune responses to SARS-CoV-2 spike protein. (EUROIMMUN, Mountain Lakes, New Jersey and Roche Diagnostics, Indianapolis, IN).Modified-Poisson regression models were used to calculate prevalence rate ratios (PRR) and 95% confidence intervals (CI) to identify sociodemographic and clinical risk factors.

Results

PROMOTE samples from 918 mothers and 1237 children were analysed. Overall, maternal SARS-CoV-2 seropositivity was 60.1% (95% CI: 56.9 -63.3) and 41.5% (95%CI: 38.8 – 44.2) for infants. Non-breastfeeding mothers had a 31% higher risk of SARS-CoV-2 seropositivity compared to breastfeeding mothers (aPRR=1.31, 95%CI: 1.08-1.59). WLHIV with undetectable viral load had a 10% increased risk of SARS-CoV-2 seropositivity (aPRR=1.10, 95%CI: 0.89-1.37). Moreover, those who were normotensive had 12% increased risk SARS-CoV-2 seropositivity (aPRR= 1.12, 95% CI: 0.68-1.85) compared to women with hypertension.Children between 2 and 5 years had a 19% reduced risk of SARS-CoV-2 seropositivity (aPRR=0.81, 95%CI: 0.64-1.02) when compared to younger children. Mother/infant SARS-CoV-2 serostatuses were discordant in 346/802 (43.1%) families tested: mothers+/children- in 72.3%; mothers-/children+ in 26.3%; child+/sibling+ concordance was 34.6%.

Conclusions

These SARS-CoV-2 seropositivity data indicate that by late 2021, about 60% of mothers and about 40% of children in a cohort of HIV-affected families in eastern/southern Africa had been infected with SARS-CoV-2. More mothers than their infants tested SARS-CoV-2+, likely due to a greater external exposure for mothers linked to daily routines/employment, and school closures. Breastfeeding was protective for mothers, likely because of the need to stay home for young children, and thus less exposure. Discordant results between children within the same families underscores the need to further understand transmission dynamics within households.

SARS-CoV-2

seropositivity

WLHIV

children

The World Health Organization (WHO) declared the SARS-CoV-2 outbreak a global pandemic on March 11, 2020, following the emergence of a cluster of pneumonia cases in Wuhan, China in December 2019. The disease was later named COVID-19, whose aetiological agent was identified as a novel coronavirus (SARS-CoV-2) (Chan et al.,2020). By May 2023, an estimated 765 million people had been infected by SARS-CoV-2 globally, with 8 million deaths recorded, a combined 174 000 of these in 47 African countries (WHO 2023). COVID-19 statistics in resource-limited settings is largely collated from national testing programs driven by clinical symptoms and thus may underestimate true spread of the disease. Consequently, there is a paucity of SARS-CoV-2 seropositivity data in the African region and most importantly among people living with HIV (PLWH) who may be at a higher risk of COVID-19 complications/mortality due to underlying compromised immunity.

Current data do not suggest higher SARS-CoV-2 infection rates among PLWH (del Amo et al.,2020; Tesoriero et al.,2021; Vizcarra et al.,2020; Huang et al.,2020) which corroborates findings from an earlier study of blood donor samples in Uganda which reported significantly lower seropositivity to S antibody among HIV-seropositive individuals. Furthermore, some studies assessing COVID-19 severity among PLWH showed no clear evidence of poorer outcomes (Cooper et al.,2020). However, emerging data is reporting higher risk of morbidity (Tesoriero et al.,2021) and mortality (Bhaskaran et al.,2021; Boulle et al.,2020; Bertagnolio et al.,2021; Geretti et al.,2020) among some HIV-SARS-CoV-2 co-infected patients, particularly those with low CD4 cell counts and unsuppressed HIV viraemia (Hoffmann et al.,2020; Dandachi et al.,2020). Some studies have also postulated that use of some antiretroviral drugs may offer protection against severe outcomes among HIV/SARSCoV-2 co-infected patients (del Amo et al.,2020; Cao et al.,2020; Zanella et al.,2021). In resource-limited settings with high background endemic infections, PLWH may be at greater risk of severe disease given the high prevalence of TB and malaria that may exacerbate both HIV and COVID-19 co-morbidities (Ambrosioni et al.,2021).

COVID-19 vulnerability has been linked to social and structural determinants like poverty, population density, and lack of access to health services, generating a syndemia of social and health related challenges (Sachs et al.,2020). In this regard, PLWH share many structural factors for heightened SARS-CoV-2 acquisition and severity of the co-infection. PLWH have been shown to have a higher predisposition to respiratory infections due to compromised immunity when compared to the general population (Chang et al.,2013).

Data on population-level exposure and immunity to SARS-CoV-2 are fundamental in understanding transmission dynamics, assess population level susceptibility, and inform public health responses. Notably, estimating the proportion of the population that has been infected, particularly in resource-constrained settings, is compounded by asymptomatic or subclinical infections, inadequate testing capacity, and challenges in collecting routine surveillance data (Arora et al.,2021). Seropositivity surveys can overcome these issues by identifying antibody responses that reflect prior SARS-CoV-2 exposure.

The PEPFAR-PROMOTE study was a longitudinal five-year follow-up roll over protocol that enrolled mothers living with HIV and their HIV exposed children previously enrolled in the IMPAACT PROMISE perinatal clinical trial from eight high enrolling African sites in the PROMISE trial (NCT01061151/NCT01253538). The PROMOTE study which began in 2016 enrolled 3771 mothers and children across the eight sites in Malawi, Uganda, Zimbabwe, and South Africa. The aims of the PROMOTE study were to follow-up on maternal and child health and survival over five years of PROMOTE follow up; assess factors that affect their morbidity and mortality; maternal adherence over time to lifetime ART, longer term complications related to the HIV disease progression, ART, and co-infections among mothers living with HIV; as well as health, survival, growth, and developmental outcomes among their HIV exposed but uninfected children (Taha et al.,2018). In the current study, we retrospectively conducted a SARS-CoV-2 seropositivity descriptive study to determine sociodemographic and clinical risk factors, maternal and pregnancy outcomes among Women Living with HIV (WLHIV) and their infants enrolled in the PEPFAR-PROMOTE observational cohort in Uganda, Malawi, and Zimbabwe. For the seropositivity surveillance analyses, data from 918 mothers and 1237 children from these sites (Malawi (Blantyre), Uganda and Zimbabwe) were included.

Study design and participants

We conducted a retrospective, cross-sectional survey to estimate SARS-CoV-2 antibody prevalence within the PEPFAR-PROMOTE observational cohort study in the midst of the COVID-19 pandemic in Eastern and Southern Africa; and before widespread COVID-19 immunisation in Malawi, Uganda, and Zimbabwe were available. The most recent or study exit visit sample was tested for each participant. All PROMOTE study participants exited the study between July 2020 and November 2021. All sites are in urban/semi-urban settings; and all women enrolled in PROMOTE were on lifelong antiretroviral therapy (ART) that conform with each country's national guidelines as the prevailing standard of care and are not provided by the study (Taha et al.,2018).

Study procedures

In the PROMOTE study, maternal follow-up evaluations were conducted every six months to collect data on medical history, ART use and adherence, physical examination (including weight and height), laboratory test results, and new events occurring between visits. The laboratory evaluations included viral load (HIV RNA PCR) testing every six months and complete blood count (CBC), CD4 + cell count, and serum chemistry (ALT, creatinine, and creatinine clearance) every 12 months. Blood was collected at scheduled six-monthly visits and processed plasma was stored at -80°C at the participating laboratories.

Laboratory methods

Available stored plasma samples from 918 mothers and 1237 children enrolled during PEPFAR-PROMOTE study collected between July 2020 and November 2021 were included in this analysis. For Malawi and Zimbabwe cohorts, plasma was tested using the EUROIMMUN Anti-SARS-CoV-2 ELISA (IgG) antibody assay following kit-specific instructions (EUROIMMUN, Mountain Lakes, New Jersey). The EUROIMMUN Anti-SARS-CoV-2 ELISA (IgG) is an enzyme-linked immunosorbent assay intended for the qualitative detection of IgG class antibodies to SARS-CoV-2 to the Spike-1 protein.

For the Uganda cohort, plasma samples were tested with the Roche SARS-CoV-2 IgG antibody test kits, according to the package insert using the anti-SARS-CoV-2 immunoassay (Roche Diagnostics, Indianapolis, IN) for the qualitative detection of antibodies to SARS-CoV-2. The assay uses a recombinant protein representing the nucleocapsid (N) antigen for the determination of antibodies against SARS-CoV-2. The test is used as an aid in identifying individuals with an adaptive immune response to SARS-CoV-2, indicating recent or prior infection. The samples were also tested according to the package insert using the antiSARSCoV-2 S electrochemiluminescence immunoassay (Roche Diagnostics) for qualitative and semi-quantitative detection of antibodies to SARSCoV-2 spike (S) protein receptor binding domain (RBD) in human serum and plasma.

Statistical analysis

Maternal and infant overall SARS-CoV-2 prevalence and 95% confidence intervals (CI) were calculated and reported. The confidence intervals were calculated using the score test method (Agresti et al.,1998). We utilised modified-Poisson regression models to calculate prevalence rate ratios (PRR) and 95% confidence intervals (CI) to identify marginal and conditional sociodemographic and clinical risk factors associated with SARS-CoV-2 seropositivity. Each univariable model included country. Each multivariable model included country and maternal risk factors including maternal age, employment status, marital status, level of education, availability of tap water at home, the distance between clinic and home, whether women have hypertension or not, whether they are breastfeeding or not, ART regimen and viral load. Children risk factors included country and age of the infant. SAS version 9.4 (SAS Institute, Cary, NC) was used for analyses.

Ethical Considerations

The PROMOTE study was approved by all relevant institutional review boards (IRBs) and women signed a written informed consent form to enroll and be followed-up with their children for five years and to provide study samples as part of their every six-month evaluation. Only samples from participants who provided consent for testing on stored samples were included in this analysis.

The study analysed samples from a total of 2155 participants (918 mothers and 1237 children) from 3 countries (Zimbabwe – 925, Malawi – 649 and Uganda-581) collected between July 2020 and November 2021 (Fig 1). The Baseline characteristics were comparable between participants testing positive (+) and negative (-) for SARS-CoV-2 Ab (Table 1)

Table 1A & B: SARS-CoV-2 antibody seropositivity for mothers (A) and their children (B) across different characteristics and distribution of variables across the two groups

A	Variable	Level	Positive (N=552)	Negative (N=366)

	Country, n (%)	Uganda	131 (46.5%)	151 (53.5%)
		Malawi	160 (61.1%)	102 (38.9%)
		Zimbabwe	261 (69.8%)	113 (30.2%)

	Age (years), median (IQR) †*		36 (33 - 40)	36 (32 - 39)

	Marital status, n (%)	No regular partner	19 (52.8%)	17 (47.2%)
		Primary regular partner	65 (54.2%)	55 (45.8%)
		Married	386 (62.6%)	231 (37.4%)
		Separated	35 (52.2%)	32 (47.8%)
		Divorced	15 (57.7%)	11 (42.3%)
		Widowed	32 (61.5%)	20 (38.5%)

	Highest level of education, n (%)	No schooling	11 (42.3%)	15 (57.7%)
		Primary-partially completed	101 (54.6%)	84 (45.4%)
		Primary-completed	54 (58.1%)	39 (41.9%)
		Secondary-partially completed	179 (59.7%)	121 (40.3%)
		Secondary completed	192 (69.3%)	85 (30.7%)
		College/University	15 (40.5%)	22 (59.5%)

	Employment status, n (%)	Formal employment	71 (55.5%)	57 (44.5%)
		Self-employment (Small business)	235 (60.6%)	153 (39.4%)
		Not employed/housewife	246 (61.2%)	156 (38.8%)

	No. people sleep in your room, median (IQR)*		3 (2 - 3)	3 (2 - 4)
	No. of children alive at baseline, median (IQR)*		3 (2 - 3)	3 (2 - 4)

	Currently breastfeeding, n (%) †	Yes	55 (48.2%)	59 (51.8%)
		No	497 (61.8%)	307 (38.2%)

	BMI (kg/m²), median (IQR)^b†*		27.0 (23.3 - 31.4)	26.1 (23 - 30.4)

	Tap water in the premises, n (%)	Yes	339 (62.7%)	202 (37.3%)
		No	213 (56.5%)	164 (43.5%)

	Travel time to the clinic, n (%)	Less than 30 minutes	156 (67.0%)	77 (33.0%)
		30-60 minutes	225 (61.6%)	140 (38.4%)
		1-2 hours	133 (56.1%)	104 (43.9%)
		Greater than 2 hours	38 (45.8%)	45 (54.2%)

	Viral load (copies/ml), n (%)^a†	Detectable	36 (56.3%)	28 (43.8%)
		Undetectable (incl <20:<40)	516 (60.4%)	338 (39.6%)

	ART regimen, n (%)†	EFV/NVP based	70 (59.3%)	48 (40.7%)
		DTG based	446 (60.8%)	288 (39.2%)
		Lpv/r, ATV/r, RTV based	29 (51.8%)	27 (48.2%)
		Other	1 (100.0%)	0
		Stopped ART	6 (66.7%)	3 (33.3%)

	Hypertension, n (%)†	No	545 (60.2%)	361 (39.8%)
		Yes	7 (58.3%)	5 (41.7%)


B	Variable	Level	Positive (N=513)	Negative (N=724)

	Country, n (%)	Uganda	65 (21.7%)	234 (78.3%)
		Malawi	181 (46.8%)	206 (53.2%)
		Zimbabwe	267 (48.5%)	284 (51.5%)

	Age group, (years) n(%)^†	<2	63 (42.9%)	84 (57.1%)
		2-5	106 (35.9%)	189 (64.1%)
		>5	344 (43.3%)	451 (56.7%)

	Sex, n(%)	Male	233 (38.3%)	375 (61.7%)
		Female	280 (44.5%)	349 (55.5%)

^a886 (96.5%) has VL done on the day of sample collection.

^b908 (98.9%) had BMI done on the day of sample collection

† Measurements done on or before sample collection.

* Represents median for each group.

Overall, maternal SARS-CoV-2 seropositivity was 60.1% (95% CI: 56.9 -63.3) and 41.5% (95% CI: 38.8 – 44.2) for infants. Country-specific SARS-CoV-2 seropositivity ranged between 46.5% to 69.8% among women and between 21.7% and 48.5%. Figure 2A-C shows the rates of SARS-CoV-2 antibody seropositivity over time and the periods during which COVID-19 vaccination was launched for each country.

SARS-CoV-2 antibody seropositivity estimates over time for Malawi, Uganda, and Zimbabwe

Mothers who were not breastfeeding prior to sample collection were associated with a 31% (aPRR=1.31, 95%CI: 1.08-1.59) increased risk of SARS-CoV-2 seropositivity compared to those who were breastfeeding. Mothers with undetectable viral load had a 10% increased risk of SARS-CoV-2 seropositivity (aPRR=1.10, 95%CI: 0.89-1.37). Moreover, those who were not hypertensive had 12% increased risk SARS-CoV-2 seropositivity (aPRR= 1.12, 95% CI: 0.68-1.85) compared to those with hypertension (Table 2).

Children between 2 and 5 years had a 19% reduced risk of SARS-CoV-2 seropositivity (aPRR=0.81, 95%CI: 0.64-1.02) when compared to younger children. Mother/infant SARS-CoV-2 serostatuses were discordant in 346/802 (43.1%) families tested: mothers+/children- in 72.3%; mothers-/children+ in 26.3%; child+/sibling+ concordance was 34.6%.

Table 2. Maternal factors associated with SARS-CoV-2 seropositivity.

Variable	PRR* (95% CI)		aPRR(95% CI)	p-value
Age (5 years increase)	1.01 (0.96-1.06)	0.611	1.01 (0.95-1.08)	0.703
Primary school complete (ref: incomplete)	1.06 (0.91-1.23)	0.476	1.05 (0.90-1.22)	0.565
Married/regular partner (ref: not married)	1.05 (0.92-1.21)	0.447	1.05 (0.92-1.20)	0.495
Tap water at home (ref: No)	1.05 (0.94-1.17)	0.356	1.03 (0.92-1.15)	0.59
Travel <1 hour to clinic (ref: ≥1 hour)	1.06 (0.94-1.20)	0.341	1.03 (0.91-1.17)	0.634
Employment (ref: unemployed)
Formal employment	0.99 (0.84-1.18)	0.929	0.98 (0.82-1.16)	0.796
Self employed	1.05 (0.94-1.17)	0.411	1.04 (0.93-1.17)	0.453
For every additional person sleeping in your room	1.02 (0.97-1.08)	0.41	1.03 (0.97-1.09)	0.293
For every additional child alive at baseline	1.00 (0.95-1.04)	0.821	0.98 (0.93-1.04)	0.592
Not breastfeeding (ref: Yes)	1.32 (1.09-1.60)	0.005	1.31 (1.08-1.59)	0.007
Undetectable viral load (ref: Detectable)	1.10 (0.89-1.36)	0.387	1.10 (0.89-1.37)	0.373
ART regimen (ref: EFV based regimen)
DTG based regimen	1.03 (0.88-1.21)	0.723	1.02 (0.87-1.19)	0.843
PI based regimen	1.02 (0.76-1.36)	0.914	1.01 (0.75-1.37)	0.925
No Hypertension (ref: Hypertension)	1.13 (0.69-1.84)	0.63	1.12 (0.68-1.85)	0.648
PRR: prevalence rate ratio, *each of the univariable models and a multivariable model were adjusted for the country variable. Modified-Poisson regression models was used to calculate prevalence rate ratio and 95% CI.

Our data show that by November 2021, about 60% of mothers and about 40% of children in a cohort of HIV-affected families in eastern/southern Africa had been infected with SARS-CoV-2. The highest SARS-CoV-2 antibody seropositivity rates stood at 69.8% and 48.5% for WLHIV and children who were enrolled in the PROMOTE study in Zimbabwe respectively. In Malawi, we report 61.1% and 46.8% SARS-CoV-2 in WLHIV and their children at the end of October 2021. The seropositivity rates in our study are much higher than the 53% seropositivity estimate reported from a sample of blood donors which suggests higher rates of SARS-Cov-2 infection among WLHIV relative to the general population over this period (Bloch et al.,2023). For Uganda, our study shows much lower SARS-CoV-2 antibody seropositivity rates of 46.5% in WLHIV and 21.7% in children. The SARS-CoV-2 seropositivity rates in the Ugandan PROMOTE cohort were much lower than the 67.7% reported from another cohort during the same period (Briggs et al.,2023). The lower antibody seropositivity rates in Uganda may be attributable to a number of factors strict implementation of non-pharmaceutical Interventions such as hand washing, social distancing, wearing masks, prolonged school closures and partly due to the later emergence of COVID in that country. The Ugandan legislative framework enacted laws that resulted in implementation of broad public health measures restricting movement of vehicles, vessels, and aircraft; closure of international borders (except for cargo); closure of education facilities; closure of places of prayers; curfew, and mandatory wearing of facial masks (Achan et al.,2023). Striking similarities in infection rates between Malawi and Zimbabwe for both mothers and children may be related to overlapping cultural and socio-behavioural norms between the two countries and similar timing of the pandemic emerging in both countries.

Our study was conducted when COVID-19 vaccination coverage was still extremely low in all 3 countries. The Zimbabwean Government rolled out COVID-19 vaccination in February 2021 with priority being given to health care workers. By the end of October 2021, only 10% of the Zimbabwean population had been vaccinated (Line et al.,2023). The PROMOTE study recruited participants mainly from informal dwellings and peri-urban areas who did not have ready access to COVID-19 vaccination until late 2021 and thus the vaccination rates are likely to be much lower in this group during the time that our study was conducted. COVID-19 vaccination program in Malawi was launched on 11 March 2021, however the Government`s heavy reliance on COVAX for vaccine supply hugely constrained its rollout; and there were only small, sporadic shipments of AstraZeneca, Johnson & Johnson, and Pfizer vaccines. As a result, the COVID-19 vaccine coverage only reached 3% by November 2021. COVID-19 vaccination rates in Uganda were low with only 2% of the population being vaccinated at the end of August 2021 (Lines et al.,2023). These data show that although COVID-19 vaccination started during a period that overlaps with our study, vaccination rates were extremely low and unlikely to affect the SARS-CoV-2 serostatus data generated. Additionally, for Uganda, testing was also done using recombinant protein representing the nucleocapsid (N) antigen which was able to confirm COVID-19 infection as opposed to seropositivity due only to spike protein due to vaccine.

Our results showed a comparable risk of SARS-CoV-2 antibody seropositivity among WLHIV who were on DTG and PI based regimens when compared to those on EFV. This finding is supported by findings from previously published studies which reported no differences in SARS-CoV-2 prevalence between PLWHIV on different ART regimens, suggesting ART does not offer differential protection against SARS-CoV-2 infection (Byrd et al.,2020; Inciarte et al.,2020; Shalev et al.,2020). However, a study by Del Amo et al reported lower risk of infection and related hospitalisation in patients receiving TDF/FTC than those receiving other regimens suggesting the ART regimen has an impact on risk of SARS-CoV-2 infection (Del Amo et al.,2020).

Risk factors for post-acute sequelae of SARS-CoV-2 infection (PASC) have generated interest, with recent evidence showing that vaccination reduces but does not exclude the risk of PASC or “long COVID” (Antonelli et al.,2022). Considering concerns about higher COVID-19 (Brown et al.,2021), increased frequency of autoimmune conditions (Rutishauser et al.,2017), other medical comorbidities, and sub optimal vaccine responses among PLWH, further research to ascertain longer-term COVID-19 outcomes among PLWH on different ART regiments is urgently needed.

The current study showed slightly higher SARS-CoV-2 prevalence in children below the age of two years and those above the age of five years compared to the age groups between two and five years. These results partly corroborate findings from a study by Huete-Pérez et al that reported higher SARS-CoV-2 rates in children below 5 years when compared to older counterparts in Nicaragua (Huete-Pérez et al.,2021. The high rates of infection in the age groups below two years and those above 5 years maybe be due to the kids above 5 years attending school and interacting with peers outside the home during the pandemic. The mother/infant SARS-CoV-2 antibody results which show that more mothers were infected than their infants may explain high seropositivity for children below two years of age who spent a significant amount of time within the mothers for care and this gives an insight into complex household transmission dynamics that require further investigation. One likely explanation for higher rates of seropositivity in mothers could be the greater need for them to undertake daily routines such as going to work against a background of school closures during the pandemic and increasing risk of infection through out of the home interactions. The strengths of our study include the relatively large sample size and robust demographic and clinical data generated during execution of the PEPFAR PROMOTE study. Furthermore, we used a testing methodology which has been rigorously validated on thousands of samples with high accuracy and precision.

Our study has some limitations. Most participants included in our analysis were on highly active antiretroviral therapy and suppressed HIV viral load for prolonged periods. The women in our study have been in research setting for a long time and received better care and health education about infection prevention. Therefore, these findings may not be generalizable to WLHIV in the general population who may not be as empowered. Furthermore, our data are derived from three countries that experienced COVID-19 peaks at different times. Our study employed different laboratory assays across the 3 countries, with Uganda using an assay that is different from the one used in Zimbabwe and Malawi. Variability in kit sensitivity may cause slight differences in positivity rates making data comparison across countries less reliable.

We found evidence of a high rate of SARS-CoV-2 infections in Malawi and Zimbabwe following the second wave infection that occurred between July and November 2021. These SARS-CoV-2 serostatus data indicate that by late 2021, more than half of mothers and more than a third of children in a cohort of HIV-affected families in eastern/southern Africa had been infected with SARS-CoV-2. Breastfeeding women may have modified social behavioural routines that may modify their risk of contracting disease in a pandemic situation. The data also provides evidence that ART regimen does not alter risk of SARS-CoV-2 seropositivity further strengthening data that suggests that ART offers no protection against COVID-19.

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No competing interests reported.

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SARS-CoV-2 seropositivity and risk factors in African women living with HIV and their Infants

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Study procedures

Laboratory methods

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