Few studies have analyzed the frequency of new diagnoses of perinatally transmitted HIV infection in Latin American countries during the COVID-19 pandemic. This study describes the clinical and immunological characteristics, antiretroviral treatment and vaccination of a cohort of patients diagnosed with vertically transmitted HIV infection in 2018 over 3 years of follow-up during the COVID pandemic in 8 Latin American countries (PLANTAIDS). We found high morbidity and mortality due to opportunistic infections, but not due to SARS-CoV-2 infection.
The natural history of HIV infection has changed dramatically with the advent of ART: infant mortality has fallen, and disease progression has slowed considerably6. However, given the aggressiveness of HIV infection in children who do not receive ART and its accelerated progression during the first years of life, the delay in diagnosis and in the initiation of ART leads to HIV-associated deaths. Three patients died in our study, mainly owing to late diagnosis and subsequent disease progression.
In line with current international guidelines7–10, ART was initiated in practically all children in the cohort after diagnosis, regardless of the CD4 count at the time of diagnosis. Early initiation of ART (first months after diagnosis) has not only been shown to reduce mortality, although it has been associated with improved immunological recovery11,12,13, improved anthropometric parameters14,15,16, improved neurocognitive profile17,18, reduced viral reservoir19,20,21, and long-term reduction in the frequency of non-AIDS events22. In our study, we found no statistically significant differences in clinical parameters (clinical/immunological stage, opportunistic infections, hospitalizations, and mortality), immunological parameters (CD4 count, CD4%, CD4/CD8 ratio, and viral load), or psychomotor development between patients diagnosed in the first year of life (early initiation of ART) and those diagnosed later. These differences could be explained by the fact that, in many of the cases we studied, ART was initiated in the advanced stage of the disease, regardless of the age of the child. On the other hand, we did observe a statistically significant difference between the 2 groups of patients in terms of reduction in viral load between the beginning and the end of follow-up (after 3 years on ART) and increase in CD4 count in those older than 1 year. No statistically significant differences were found in CD4 counts between the first and fourth check-ups in children under 1 year of age, possibly because the range of lymphocytes considered normal decreases with age.
Based on current international guidelines7–10, initial ART in children consists of a combination of at least 3 antiretroviral drugs. In accordance with the WHO recommendations7 in force at the time of the study, we observed less frequent use of AZT (zidovudine) and LPV/r during follow-up, with a progressive trend toward incorporation of new drugs, such as integrase inhibitors (dolutegravir or bictegravir), especially in older patients. However, at the time of this study, some of these "new drugs" were not yet universally available, thus accounting for the use of outdated regimens (such as AZT or raltegravir in patients older than 1 month, EFV in children under 3 years of age…). Moreover, administration of ART to children is hampered by several obstacles23,24 that have a direct impact on adherence, as follows: a small number of approved drugs; specific dosages based on age, weight, or pubertal development; the need for special presentations (syrups, dispersible tablets); and the need for adequate palatability. In our study, only 2 patients were able to benefit from the convenience of co-formulated drugs (2 adolescent patients who were prescribed Biktarvy® [FTC-TAF-BIC]). Consistent with recent publications25, the most frequent adverse effect in our study was lipid profile abnormalities, which was associated with the use of boosted protease inhibitors or EFV.
Pediatric patients living with HIV have an increased risk of more illnesses and more severe illnesses than uninfected children; therefore, appropriate immunization during childhood is important26. In general, children should be immunized according to the vaccination schedule in force in each country. Although most vaccines have been shown to be safe and effective in HIV-infected patients27,28,29, it should be borne in mind that in the case of vaccines containing live attenuated viruses, the patient must remain asymptomatic and not immunosuppressed so that the vaccine can be administered safely. In our study, a not insignificant proportion of patients were immunized with live attenuated vaccines (12 children received yellow fever vaccine, 10 received varicella vaccine, 40 received at least 1 dose of MMR vaccine, and 23 patients received at least 1 oral dose of polio vaccine), although the immunological status of the patients at the time of administration of these vaccines is unknown. Vaccination against tuberculosis (BCG) is not usually recommended in children with HIV infection owing to the risk of disseminated mycobacterial disease after administration. However, since Latin America is considered a high incidence area for tuberculosis, the BCG vaccine is included in most of the systematic vaccination schedules. In our study, this vaccine was administered to more than a third of the patients. This is not surprising, considering that, at the time of administration of the BCG vaccine (at birth), the diagnosis of HIV infection was unknown in most of the children. Nevertheless, no significant adverse effects were observed in any patient after administration of live attenuated vaccines or BCG vaccine. These vaccination rates, together with those for the other most common preventable diseases (92.9% against HBV, 87.8% against dTP, 92.7% against Hib, and 90.2% against pneumococcus), are similar to those published in children living with HIV in Latin America30. Only 8 patients were vaccinated against SARS-CoV-2 infection.
In children, HIV infection leads to malnutrition, which in turn can lead to growth retardation, although findings differ widely depending on the geographical area and are more accentuated in middle- and low-income countries31–36. In our work, 28.3% and 51.1% of children under 5 years of age had, respectively, a weight and height percentile of less than 3 at the first check-up after diagnosis, with a slight improvement in subsequent check-ups, after several months or years in treatment. As for children older than 5 years, the figures are not so striking, and only 4.2% of the patients had a BMI in a percentile lower than 3. Although the delay in growth and lower scores than expected in terms of weight and height are the most frequent observations, some studies also present data on overweight and obesity in children living with HIV25,37. In our case, the highest number of patients under 5 years of age with a weight percentile greater than 97 (2.6%) was obtained at the second check-up, with lower figures found at the other 3 check-ups. At the second check-up, 16.7% of children older than 5 years had a BMI above the 85th percentile, which the WHO considers overweight. Therefore, in our study, we found higher rates of delayed growth (weight and height) in children under 5 years of age (with improvement after starting ART) and a greater tendency to be overweight in children over 5 years of age.
The figures observed for opportunistic infections are similar to those presented in other studies38,39, with tuberculosis being the most frequent. Confirming a diagnosis of tuberculosis in children is complicated owing to the difficulty in obtaining adequate samples (invasive procedures are usually required). In addition, microbiological tests based on culture or nucleic acid detection have low sensitivity because of the paucibacillary nature of the disease40. Thus, in our study, microbiological confirmation was only achieved in 1 patient. In the remaining cases, empirical treatment was established based on the clinical and/or epidemiological context.
Breastfeeding is not generally recommended in children living with HIV owing to the risk of disease transmission41,42,43. According to the WHO, exclusive breastfeeding should be recommended in countries where this strategy is feasible, safe, acceptable, affordable, and sustainable in order to prevent MTCT of HIV. However, in our work, we observed that somewhat less than half of the children were breastfed, and, as discussed above, the diagnosis of HIV infection was unknown in most cases at birth. Consequently, we do not know whether the infection could have been acquired through breastfeeding in these cases, thus emphasizing the importance of HIV screening in pregnancy and childbirth, as well as in cases where the mother's partner has HIV infection.
It is essential to guarantee adequate therapeutic adherence, as this enables viral suppression to be maintained44. However, this is not always easy in children. In our study, adherence was appropriate in only 85% of patients at the start of follow-up in our study, although we found statistically significant differences in the number of patients with a more advanced clinical stage and in the reduction in the number of opportunistic infections between children with adequate adherence and those without it.
It is currently unknown whether people with HIV are at increased risk of SARS-CoV-2 infection, and while studies in adults support the hypothesis that HIV is an independent risk factor for increased disease severity45, most publications, especially in children, suggest that neither HIV nor ART is associated with an increased risk of infection or clinical severity46,47,48. We recorded only 3 cases of acute SARS-CoV-2 infection, all of which involved asymptomatic or mild symptoms. However, owing to the pandemic, 3 patients were lost to follow-up. One withdrew from clinical follow-up and discontinued ART, leading eventually to disease progression and virological and immunological failure.