Introduction

SARS-CoV-2 infection, the name given to the new coronavirus, and the disease resultant from this virus, coronavirus disease 2019 (COVID-19), has been declared a global health emergency categorized as a pandemic by the World Health Organization (WHO) ¹. Like other coronaviruses, SARS-CoV-2 infects the epithelial cells of the pulmonary alveoli, producing pneumonia, although some reports have described infection in different organs and systems, including gastrointestinal symptoms, especially in children ². Although the mortality of the infection is around 5.6% currently ³, the actual burden of the disease is not yet known, and recent reports have estimated that 81% of those infected develop mild symptoms, while 14% have severe symptoms, and 5% become critically ill ⁴. As we learn more about the epidemic and infection, we have been able to establish that the most severe cases and mortality are associated with underlying health conditions, the most common being hypertension, diabetes, and cardiovascular disease ⁵. Under these circumstances, centers and clinicians around the world have wondered if there is an increased risk of morbidity and complications in immunocompromised patients ⁶. Based on the above, we consider the following review to assess current evidence regarding the impact and possible recommendations of care in an immunosuppressed population, such as that of persons with HIV. To develop the review, we relied on a series of clinical questions that allowed us, as of April 6, 2020, to develop a search for scientific literature that would help us answer them. The search was carried out on PubMed and a review of conferences, expert commentary, and recommendations in international scientific societies. Table 1 shows the search equation used in PubMed for answering the revision questions.

In patients with HIV-1 or HIV-2, what has been the epidemiology related to Coronavirus infection?

Little data is found about the impact of coronavirus infections on persons with HIV. A study in a Swiss cohort of HIV-infected patients, in which bronchoalveolar wash samples were tested for respiratory viruses, described coronaviruses and influenza A viruses as the most common ⁷. On the other hand, reviews assessing the rate of fatality due to acute respiratory infections among persons with HIV, have reported an increased risk in this group of people compared to those without such comorbidity, although without a difference in the viral etiology of the respiratory infection ⁸. Additionally, from the follow-up results of previous epidemics for Acute Severe Respiratory Syndrome (SARS), we know that persons with HIV were not the worst prognosis ⁹ and that one of the drugs used for their treatment, ritonavir-enhanced lopinavir protease inhibitor (LPV/r) in combination with ribavirin, could help decrease the incidence of failure and death in this scenario ¹⁰.

In patients infected with HIV-1 or HIV-2, what has been the epidemiology related to COVID-19 infection?

The pathogenesis of coronaviruses includes the deterioration of the immune response, especially of T lymphocytes, observing a numerical and functional depletion of LTCD4+ and CD8+ T Lymphocytes (LTCD8+), likely to be associated with a negative regulation caused by increased TNF-A, IL-6, and IL-10 ¹¹. Besides, lymphopenia has been identified as a poor prognosis factor for evolution to Acute Respiratory Failure (IRAG) and death ¹². However, in the description of several series and case reports, HIV has not been identified as common comorbidity in COVID-19 patients, with nonexistent cases of this co-infection in some scenarios ¹³, or few, including a case report describing a 61-year-old man, residing in Wuhan District, China, with a history of type II diabetes and heavy smoking, who due to his respiratory symptoms was diagnosed with COVID-19 and at the same time with HIV infection, and who within treatments received during hospitalization, had LPV/r, recovering satisfactorily from his symptoms ¹⁴. In an attempt to conduct a more systematic search, 1,178 persons with HIV were assessed in Wuhan, of which 12 had suggestive symptoms, and 8 received confirmation of SARS-CoV-2 infection. Of these, 6 had a CD4+ T-cell count (LTCD4+) greater than 350 cel/L and two people had it between 101-350 cel/L; his age was between the ages of 47 and 61; all had HIV-1 RNA <20 copies/ml, and were on treatment based on reverse transcriptase inhibitors nucleotide analog and non-nucleotide analogs; 6 of the patients had mild symptoms, one was classified as with severe symptoms and one patient died ¹⁵ . More recently, Blanco et al., reported five HIV cases from 543 consecutive admitted patients with SARS-CoV-2, all of them were male born, 29 to 49 years old, one patient was an advanced late presenter with CD4 13 cel/uL, and four were virologically suppressed at least 7 years on HAART, two with darunavir-boosted cobicistat and two dolutegravir based ART. CD4 cell counts were above 400 cells per uL in all subjects. All patients had COVID-19 clinical pictures resembling the general population, and none of these has died ¹⁶.

On the other hand, there has been speculation about possible similarities between HIV-1 and COVID-19 proteins, which after analyzing the suggested sequences shared, were specific to either of the two viruses ¹⁷. In other series, persons with HIV have represented between 0-1.4% ^18-21. These studies draw attention to the apparent lack of association between HIV and an increased risk for progression to IRAG or death, questioning even whether the risk could be even lower than in the general population. In such studies, factors such as low LTCD4+ count, high HIV RNA level, or antiretroviral regimen have not been identified as apparent risk factors.

Among the possible causes that explain these findings, could be differences in receptors through HIV and pathogenic coronaviruses enter the target cell in humans, or, the form of assembly and encapsulation of each virus, since HIV is performed near the cytoplasmic membrane, and in coronavirus, the process is carried out in the endoplasmic reticulum, which may represent that there is no synergistic or cooperative pathogenesis ²².

In persons with HIV-1 or HIV-2, what therapeutic options are available for coronavirus co-infections?

At the time of writing this paper, there are 1,518 clinical studies inscribed clinicaltrials.gov, including most designed to establish the effectiveness of various medicines in the treatment of COVID-19. Strategies based on umifenovir (Arbidol), LPV/r, ribavirin plus interferon-alpha 1b, darunavir/cobicistat, baloxavir marboxil, azvudin, remdesivir, hydroxychloroquine; however, most of these studies are planned to end in one to 11 months, and the results will be only known at the end of this time or through internal analyses ²³. The most promising antiviral is remdesivir, an adenosine nucleotide-like pro-drug with broad-spectrum antiviral action that has been shown in non-human primates that it can prevent viral replication into respiratory tissue and the evolution of clinical symptoms ²⁴, and already has human safety studies ²⁵. No clinical studies discussing specific therapy of COVID19 or other Coronaviruses in persons with HIV are available; however, the question about the relationship between therapeutic options for COVID-19 treatment and antiretroviral drugs has generated a lot of interest. Patients infected with SARS, who received LPV/r in combination with ribavirin, had lower mortality and severe respiratory distress syndrome, compared to historical controls ²⁶. In MERS, the combination of Ribavirin and Interferon-b has shown increased in-vitro antiviral activity compared to LPV/r ²⁷. Based on this, the initial results of a systematic review on this topic have recently been published, in which 22 observational studies and a clinical trial conducted to assess the effectiveness of the use of antiretrovirals in these infections have been published; of the 20 studies that reported outcomes, three did so with SARS, 6 with MERS and 11 with COVID-19, most using LPV/r; however, all studies had limitations in terms of having a small sample size, and having no control group, except in two studies wherein one, the controls were historical ²⁸. In the only randomized clinical trial conducted with the use of antiretrovirals, 99 patients with severe COVID-19 infection were randomly assigned to receive LPV/r plus the treatment standard for 14 days and 100 patients to receive the standard of treatment, which could include one or more treatments between supplemental oxygen, invasive and noninvasive ventilation, antibiotics, vasopressors, renal replacement therapy, and oxygenation through an extracorporeal membrane. 28-day mortality was numerically lower in the group receiving LPV/r (14/99 compared to 25/100); however, this was not statistically significant. The use of LPV/r was not associated with differences in time to clinical improvement, albeit its use within the first 12 days of symptoms reduced the time to clinical improvement, stay in ICU in 5 days and mortality ²⁹. The use of other protease inhibitors in combination with ritonavir or cobicistat has been postulated; however, there is no evidence of clinical or in vitro activity against SARS-CoV-2, and some of them may have interactions with drugs used in conditions such as hypertension and diabetes ³⁰.

Role of antiretrovirals in the prophylaxis of COVID-19 infection

One theory to explain the low proportion of HIV/COVID-19 co-infection cases has been the possible protective role of antiretrovirals as prophylactics. So far, there is no clarity whether protease inhibitors can inhibit cysteine 3-protease, similar to chymotrypsin, an enzyme involved in the maturation of SARS ³¹. Additionally, a large proportion of patients receive antiretroviral therapy (ART) schemes based on Non-Nucleoside Reverse Transcriptase Inhibitors (ITRNn) or integrase inhibitors, which could suggest that there is another cause related to the apparent lower risk of infection and evolution to IRAG. Two studies have assessed a possible protective effect of LPV/r as post-exposure prophylaxis in SARS and MERS infections; however, variations in design and limitations in sample size, as well as lack of information about the intensity of exposure, do not allow conclusions to be drawn as to this effect ²⁸.

Discussion

Based on the previous review, we consider that with the available evidence, it is possible to advance some discussions against the following topics:

Conclusions

The rapid and progressive expansion of the COVID-19 pandemic globally takes place amid the still-growing HIV pandemic; however, the effects of the interaction of these two infections are not yet clear from the scarcity of data and reports, without an evident negative impact on the health of persons with HIV. The spread of SARS-CoV-2 has mainly reached Asian and European countries with robust and functional health systems, strong economies, and better control of HIV infection in terms of morbidity and virological suppression. In contrast, the COVID-19 pandemic is expected to cause a great health impact on the African continent, particularly for people with HIV. Africa is currently sheltering 70% of the HIV-infected population worldwide, and the highest number of deaths; however, the reason why this continent has a relatively low number of cases of COVID-19 infection is still elusive ³⁴. It is equally feasible that, in Colombia and Latin America, with high rates of late presentation of HIV infection, mortality, and continued significant distance from the UNAIDS targets of 90 90 90 ³⁵, persons with HIV in the region are particularly vulnerable to the effects of SARS-CoV-2. For this reason, it is a priority to maintain close monitoring in the care of this population with information and continuing education strategies, emphasizing optimal adherence to ART and measures to prevention against the contagion by monitoring and supporting the multidisciplinary program with optimized communication technologies, to achieve the objectives of early identification of COVID-19 symptoms, its early diagnosis and treatment and the prevention of critical or fatal outcomes by co-infection with this new coronavirus. It is crucial to expand knowledge of the effects of COVID-19 on HIV infection at the local, regional, and global levels.