Cardiac and Renal Comorbidities in Aging People Living With HIV.

Contemporary World Health Organization data indicates that ≈39 million people are living with the human immunodeficiency virus. Of these, 24 million have been reported to have successfully accessed combination antiretroviral therapy. In 1996, the World Health Organization endorsed the widespread use of combination antiretroviral therapy, transforming human immunodeficiency virus infection from being a life-threatening disease to a chronic illness characterized by multiple comorbidities. The increased access to combination antiretroviral therapy has translated to people living with human immunodeficiency virus (PLWH) no longer having a reduced life expectancy. Although aging as a biological process increases exposure to oxidative stress and subsequent systemic inflammation, this effect is likely enhanced in PLWH as they age. This narrative review engages the intricate interplay between human immunodeficiency virus associated chronic inflammation, combination antiretroviral therapy, and cardiac and renal comorbidities development in aging PLWH. We examine the evolving demographic profile of PLWH, emphasizing the increasing prevalence of aging individuals within this population. A central focus of the review discusses the pathophysiological mechanisms that underpin the heightened susceptibility of PLWH to renal and cardiac diseases as they age.

Human Immunodeficiency Virus Infection Impairs Th1 and Th17 Mycobacterium tuberculosis-Specific T-Cell Responses.

Background: Human immunodeficiency virus (HIV)-infected individuals have a higher risk of developing active tuberculosis (TB) than HIV-uninfected individuals, but the mechanisms underpinning this are unclear. We hypothesized that depletion of specific components of Mycobacterium tuberculosis (Mtb)-specific CD4+ and CD8+ T-cell responses contributed to this increased risk. Methods: Mtb-specific T-cell responses in 147 HIV-infected and 44 HIV-uninfected control subjects in a TB-endemic setting in Bloemfontein, South Africa, were evaluated. Using a whole-blood flow cytometry assay, we measured expression of interferon gamma, tumor necrosis factor alpha, interleukin 2, and interleukin 17 in CD4+ and CD8+ T cells in response to Mtb antigens (PPD, ESAT-6/CFP-10 [EC], and DosR regulon-encoded α-crystallin [Rv2031c]). Results: Fewer HIV-infected individuals had detectable CD4+ and CD8+ T-cell responses to PPD and Rv2031c than HIV-uninfected subjects. Mtb-specific T cells showed distinct patterns of cytokine expression comprising both Th1 (CD4 and CD8) and Th17 (CD4) cytokines, the latter at highest frequency for Rv2031c. Th17 antigen-specific responses to all antigens tested were specifically impaired in HIV-infected individuals. Conclusions: HIV-associated impairment of CD4+ and CD8+Mtb-specific T-cell responses is antigen specific, particularly impacting responses to PPD and Rv2031c. Preferential depletion of Th17 cytokine-expressing CD4+ T cells suggests this T-cell subset may be key to TB susceptibility in HIV-infected individuals.

Critical illness due to infection in people living with HIV.

People living with HIV comprise a substantial number of the patients admitted to intensive care. This number varies according to geography, but all areas of the world are affected. In lower-income and middle-income countries, the majority of intensive care unit (ICU) admissions relate to infections, whereas in high-income countries, they often involve HIV-associated non-communicable diseases diagnoses. Management of infections potentially resulting in admission to the ICU in people living with HIV include sepsis, respiratory infections, COVID-19, cytomegalovirus infection, and CNS infections, both opportunistic and non-opportunistic. It is crucial to know which antiretroviral therapy (ART) is appropriate, when is the correct time to administer it, and to be aware of any safety concerns and potential drug interactions with ART. Although ART is necessary for controlling HIV infections, it can also cause difficulties relevant to the ICU such as immune reconstitution inflammatory syndrome, and issues associated with ART administration in patients with gastrointestinal dysfunction on mechanical ventilation. Managing infection in people with HIV in the ICU is complex, requiring collaboration from a multidisciplinary team knowledgeable in both the management of the specific infection and the use of ART. This team should include intensivists, infectious disease specialists, pharmacists, and microbiologists to ensure optimal outcomes for patients.

Optimizing the Treatment of Invasive Candidiasis-A Case for Combination Therapy.

Invasive candidiasis is a rising global health threat with increasing incidence, persistently high mortality, and diminishing treatment options. Antifungal resistance has rapidly emerged and spread, with multidrug-resistant species deemed an urgent and serious threat. While acknowledging the key role of antifungal stewardship and infection control in curbing spread, we examine the role of antifungal monotherapy in driving resistance and the potential for combination therapy to prevent stress adaptation and emergence of drug resistance. In addition to its role in mitigating resistance, combination treatment may improve drug penetration, expedite fungal clearance, and allow lower, less toxic doses of individual drugs to be used. A growing body of laboratory-based evidence suggests that antifungal combinations can yield synergistic activity against Candida spp., including against frequently multidrug-resistant Candida auris. It is imperative to test these combinations in clinical trials, incorporating resistance end points as a marker of success.

Non-typhoid Salmonella endocarditis complicated by cardiac failure and acute limb ischaemia in a person living with HIV and hepatitis C: A case report and literature review.

Salmonella infections are responsible for a large burden of disease worldwide. Non-typhoidal Salmonella (NTS) species cause a myriad of disease manifestations, particularly amongst severely immunocompromised individuals. We present a rare case of endocarditis caused by the NTS species Salmonella Enteritidis in an individual living with HIV and hepatitis C. In this case, endocarditis was complicated by embolization and acute arterial occlusion of the left arm, as well as mitral valve perforation resulting in cardiac failure. A review of the available literature shows few cases of NTS causing endocarditis in people living with HIV, with the earliest reported case in 1983. Our case demonstrates the potential complications of NTS endocarditis and highlights the importance of evaluating patients with NTS-associated blood stream infection for cardiovascular involvement. Prompt surgical intervention in addition to appropriate antimicrobial therapy is essential to reduce the high morbidity and mortality associated with NTS endocarditis.

An audit of adherence to cervical cancer screening guidelines in a tertiary-level HIV clinic.

Background: Cervical cancer is the most common malignancy affecting South African women aged 15-44 years, with a higher prevalence among women living with HIV (WLWH). Despite recommendations for a screening target of 70%, the reported rate of cervical cancer screening in South Africa is 19.3%. Objectives: To investigate the adherence of healthcare workers to cervical cancer screening guidelines in a tertiary-level HIV clinic. Method: A retrospective cross-sectional record audit of women attending the Charlotte Maxeke Johannesburg Academic Hospital HIV Clinic over a 1-month period. Results: Out of 403 WLWH who attended the clinic, 180 (44.7%) were screened for cervical cancer in the 3 years prior to the index consultation. Only 115 (51.6%) of those women with no record of prior screening were subsequently referred for screening. Women who had undergone screening in the previous 3 years were significantly older (47 years vs 44 years, P = 0.046) and had a longer time since diagnosis of their HIV (12 years vs 10 years, P = 0.001) compared to women who had not undergone screening. There was no significant difference in CD4 count or viral suppression between women who had and had not undergone screening. Conclusion: The rate of cervical cancer screening in our institution is below that recommended by the World Health Organization and the South African National Department of Health.

Coronavirus Host Genomics Study: South Africa (COVIGen-SA).

Host genetic factors are known to modify the susceptibility, severity, and outcomes of COVID-19 and vary across populations. However, continental Africans are yet to be adequately represented in such studies despite the importance of genetic factors in understanding Africa's response to the pandemic. We describe the development of a research resource for coronavirus host genomics studies in South Africa known as COVIGen-SA-a multicollaborator strategic partnership designed to provide harmonised demographic, clinical, and genetic information specific to Black South Africans with COVID-19. Over 2,000 participants have been recruited to date. Preliminary results on 1,354 SARS-CoV-2 positive participants from four participating studies showed that 64.7% were female, 333 had severe disease, and 329 were people living with HIV. Through this resource, we aim to provide insights into host genetic factors relevant to African-ancestry populations, using both genome-wide association testing and targeted sequencing of important genomic loci. This project will promote and enhance partnerships, build skills, and develop resources needed to address the COVID-19 burden and associated risk factors in South African communities.

Age significantly influences the sensitivity of SARS-CoV-2 rapid antibody assays.

BACKGROUND: Point-of-care serological assays are a promising tool in COVID-19 diagnostics but do have limitations. Our study evaluated the sensitivity of five rapid antibody assays and explored factors influencing their sensitivity in detecting SARS-CoV-2-specific IgG and IgM antibodies. METHODS: Finger-prick blood samples from 102 participants, within 2-6 weeks of PCR-confirmed COVID-19 diagnosis, were tested for IgG and IgM using five rapid serological assays. The assay sensitivities were compared, and patient factors evaluated in order to investigate potential associations with assay sensitivity. RESULTS: Sensitivity ranged from 36% to 69% for IgG and 13% to 67% for IgM. Age was the only factor significantly influencing the likelihood of a detectable IgG or IgM response. Individuals aged 40 years and older had an increased likelihood of a detectable IgG or IgM antibody response by rapid antibody assay. CONCLUSION: Rapid serological assays demonstrate significant variability when used in a real-world clinical context. There may be limitations in their use for COVID-19 diagnosis among the young.

Comparison of outcomes in HIV-positive and HIV-negative patients with COVID-19.

BACKGROUND: South Africa has the highest prevalence of HIV in the world and to date has recorded the highest number of cases of COVID-19 in Africa. There is uncertainty as to what the significance of this dual infection is, and whether people living with HIV (PLWH) have worse outcomes compared to HIV-negative patients with COVID-19. This study compared the outcomes of COVID-19 in a group of HIV-positive and HIV-negative patients admitted to a tertiary referral centre in Johannesburg, South Africa. METHODS: Data was collected on all adult patients with known HIV status and COVID-19, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), admitted to the medical wards and intensive care unit (ICU) between 6 March and 11 September 2020. The data included demographics, co-morbidities, laboratory results, severity of illness scores, complications and mortality, and comparisons were made between the HIV-positive and HIV negative groups. RESULTS: Three-hundred and eighty-four patients, 108 HIV-positive and 276 HIV-negative, were included in the study. Median 4C score was significantly higher in the HIV-positive patients compared to the HIV-negative patients, but there was no significant difference in mortality between the HIV-positive and HIV-negative groups (15% vs 20%, p = 0.31). In addition, HIV-positive patients who died were younger than their HIV-negative counterparts, but this was not statistically significant (47.5 vs 57 years, p = 0.06). CONCLUSION: Our findings suggest that HIV is not a risk factor for moderate or severe COVID-19 disease neither is it a risk factor for mortality. However, HIV-positive patients with COVID-19 requiring admission to hospital are more likely to be younger than their HIV-negative counterparts. These findings need to be confirmed in future, prospective, studies.

Human MAIT cells respond to and suppress HIV-1.

Human MAIT cells sit at the interface between innate and adaptive immunity, are polyfunctional and are capable of killing pathogen infected cells via recognition of the Class IB molecule MR1. MAIT cells have recently been shown to possess an antiviral protective role in vivo and we therefore sought to explore this in relation to HIV-1 infection. There was marked activation of MAIT cells in vivo in HIV-1-infected individuals, which decreased following ART. Stimulation of THP1 monocytes with R5 tropic HIVBAL potently activated MAIT cells in vitro. This activation was dependent on IL-12 and IL-18 but was independent of the TCR. Upon activation, MAIT cells were able to upregulate granzyme B, IFNγ and HIV-1 restriction factors CCL3, 4, and 5. Restriction factors produced by MAIT cells inhibited HIV-1 infection of primary PBMCs and immortalized target cells in vitro. These data reveal MAIT cells to be an additional T cell population responding to HIV-1, with a potentially important role in controlling viral replication at mucosal sites.

Maintenance of Functional CD57+ Cytolytic CD4+ T Cells in HIV+ Elite Controllers.

Cytolytic CD4+ T cells play a prominent role in chronic viral infection. CD4+ CTLs clones specific for HIV-1 Nef and Gag are capable of killing HIV-1 infected CD4+ T cells and macrophages. Additionally, HIV-specific cytolytic CD4+ T cell responses in acute HIV infection are predictive of disease progression. CD57 expression on CD4s identifies cytolytic cells. These cells were dramatically increased in chronic HIV infection. CD57 expression correlated with cytolytic granules, granzyme B and perforin expression. They express lower CCR5 compared to CD57- cells, have less HIV total DNA, and were a minor component of the HIV reservoir. A small percentage of CD57+ CD4+ CTLs from EC were HIV-specific, could upregulate IFNγ with Gag peptide stimulation, express cytolytic granule markers and maintain TbethighEomes+ transcription factor phenotype. This was not observed in viraemic controllers. The maintenance of HIV-specific CD4 cytolytic function in Elite controllers together with CD8 CTLs may be important for the control of HIV viraemia and of potential relevance to cure strategies.