Pediatric HIV Long-Term Nonprogressors

Patients infected with HIV are best categorized along a continuum from rapid progressors to HIV long-term nonprogressors. Long-term nonprogressors (LTNPs) are those in which AIDS develop many years after being infected with HIV, often beyond the 10-year mark, and represent 15–20% of the HIV infected patients. Many of these patients are able to control their infection and maintain undetectable viral loads for long periods of time without antiretroviral therapy. After a comprehensive literature search, we found extensive data related to HIV LTNPs in the adult population; however, very limited data was available related to LTNPs within the pediatric population. We present a case of pediatric HIV LTNPs, perinatally infected patient with undetectable viral loads, despite never receiving ART. Although there are not many instances of LTNPs among children, this child may be one, though she had intermittent viremia. She has continued to manifest serologic evidence of infection, with yearly ELISA and western blot positive tests. Based on the viral fitness studies that were performed, this case exemplifies an adolescent LTNP.


Introduction
When patients are infected with HIV, their disease process can be best characterized along a continuum from rapid progressors to HIV long-term nonprogressors (LTNPs). Subsets of these patients are characterized as rapid progressors, in which they develop AIDS within a few years, often less than 5 years. In contrast, long-term nonprogressors are those in which AIDS develop many years after being infected with HIV, often beyond the 10-year mark, and represent 15-20% of the HIV infected patients. LTNPs are a subset of long-term nonprogressors, generally referred to as individuals who have contracted the HIV infection but control their infection and maintain undetectable viral loads for long periods of time without antiretroviral therapy [1].
During our literature search, we found extensive data related to HIV LTNPs in the adult population; however, very limited data was available related to LTNPs within the pediatric population. It is important not to confuse pediatric LTNPs with pediatric slow progressors, as the latter is referred to a group of HIV-1-infected pediatric individuals who are homogeneous for route and length of infection and standard of care, thereby having disease progression requiring antiretroviral therapy at some point of their lives. We present a case of pediatric HIV LTNPs, perinatally infected patient with undetectable viral loads, despite never receiving ART.

Case Report
A 14-year-old female with a history of HIV acquired via vertical transmission from a noncompliant, advanced AIDSinfected mother presented to our tertiary care hospital. She had no siblings and lived with her mother for the first two  years after birth until her mother died of an AIDS-associated infection. Information regarding the HIV status of her biological father was unknown, as this individual was never involved in her care. She missed all her medical appointments while living with her mother. Afterwards, she resided with her maternal grandparents. At that time, she had her first medical evaluation without prior antepartum medical records, where an ELISA and western-blot test were done and came back positive. Her HIV-1 plasma viral load was 1,050-copies/mL and a CD4 count was 2,869 cells per cubic millimeter of blood (CUMM). HIV-1/2 antibody testing confirmed an HIV-1 infection.
She was transferred to an HIV satellite clinic and later to our tertiary infectious disease adolescent clinic. She had never taken ART prior to her MUSC visit. Tables 1 and 2 demonstrate the values of her immunodeficiency panel as well as her HIV-1 viral load since initiation of care at our center. Her repeat HIV-1 plasma RNA viral load was 632-copies/mL with a CD4 count of 2,364/cumm. She was monitored clinically without ART and serial repeat laboratory tests were performed.
Her HIV-1 plasma viral load remained undetectable and her viral load remained dramatically unchanged. Repeat ELI-SA and western blot testing performed on a yearly basis since initial HIV diagnosis have been positive (Table 2). Of note, further investigation was significant for a positive human leukocyte antigen B27 test; however, no deletions or mutations were appreciated. Additional testings for ankylosing spondylitis, reactive arthritis, sacroiliitis, uveitis, and other conditions known to have a positive HLA-B27 antigen test were negative. Proviral HIV tropism testing confirmed a CCR5-tropic (R5) using HIV-1 virus.
Two years later, her viral load rose to 614-copies/mL of plasma. Her viral load remained between undetectable and 727-copies/mL and her CD4 ranged from 1151 to 2186/cumm despite not being initiated on ART. Since 2005, it has remained undetectable without ART. With respect to her overall general clinical course, she has not had any complicating opportunistic infections, hospitalizations, or complications related to HIV. She is a hitherto fit girl, with all the appropriate signs of puberty and sexual development for her age group, including her height and weight.

Discussion
Pediatric long-term nonprogressors (LTNPs) are individuals infected with HIV-1 who maintain a suppressed viral load, which refers to either an undetectable viral load (HIV RNA <20 to 75 copies/mL) or a low-detectable HIV-RNA viral load (typically HIV RNA <200 copies/mL), depending on the sensitivity of the HIV RNA assay that is used, despite not being on ART [2]. The clinical relevance of the LTNP classification is not well understood, as some patients remain virologically suppressed, while others have gone on to develop AIDS. LTNPs generally remain at a certain viral load despite not receiving ART [1]. Unlike patients with a "functional" cure, these patients are once known to have detectable HIV-1 RNA viral loads, similar to our index case of ∼20,000 copies/mL of plasma, and have spontaneously suppressed their viral load and maintained a stable CD4 count without ART influence. Of importance, in comparison to LTNPs, patients with a "functional" cure would test negative for HIV at some point of their care, whereas LTNPs will always have a positive HIV test [2].
After acquisition of HIV, the virus naturally enters into human cells and attach to proteins on that cell. HIV tropism testing allows for knowledge to the type of protein that HIV attaches to. These proteins are the CCR5 and CXCR4, and most HIV infections are caused by the CCR5-using virus; however, as HIV reproduces, it may change from a CCR5using virus to a CXCR4-using virus. Mutations or deletions in these proteins can account for why an HIV-infected individual rarely progresses to AIDS. Our index patient had a CCR5-tropic using HIV-1 virus.
Different etiologies have been studied which allows longterm nonprogressors to go live without taking ART. These etiologies consist of gene and receptor mutations [3], various mitochondrial DNA types [4], and different human leukocyte antigen (HLA) types, specifically HLA-B27 or HLA-B57 [5]. Perinatally infected children with HIV may acquire the same genes and HLA as their mothers. However, since differences in transcriptional regulation have been observed among different HIV-1 subtypes, the viruses may also be very different. With our index patient, whose mother died secondary to opportunistic infections complicating her advanced AIDS, HLA antigen testing was positive for HLA-B27; however, no deletion or mutation was appreciated.
One question that arises is, was her biological father also HIV-infected? And if so, the possibility of this patient acquiring a mutated HLA B27 gene must be entertained. Unfortunately, her biological father was not involved in her care and his exact presence was unknown; therefore, testing for this was not available and therefore would remain a mystery. Although there are not many instances of LTNPs among children, this child may be one, though she had intermittent viremia. She has continued to manifest serologic evidence of infection, with yearly ELISA and western blot positive tests. Based on the viral fitness studies that were performed, this case exemplifies an adolescent LTNP.

Disclosure
This paper is not under consideration by any other journal.