Clinical and Laboratory Outcomes in HIV-1 and HTLV-1/2 Coinfection: A Systematic Review

Aim To perform a systematic review to describe the available findings on clinical outcomes in HIV-1 and HTLV-1/HTLV-2 co-infected individuals since 1995. Design This Systematic Review used PECO criteria follow by PRISMA reporting guidelines and registered as CRD42021279062 (Prospero database). The Newcastle-Ottawa Scale assessed the methodological quality of included studies. Data Collection and Analysis A systematical search in PubMed/MEDLINE, Embase, Web of Sciences databases for cross-sectional, case-control, or cohort studies design to identify clinical and laboratorial outcomes related to HIV-1 and HTLV-1/2 coinfection. Search strategy: [(“HIV-1” AND “HTLV-1” OR “HTLV-2”) AND (“Coinfection”) AND (1990/01/01:2021/12/31[Date- Publication])]. Results A total of 15 articles were included on this systematic review describing data of 2,566 mono and coinfected patients, 58% male, with mean age was 35.7 ± 5.7 years. HIV-1 and HTLV-1 coinfected patients were more likely to had shorter survival and faster progression to death or mortality than monoinfected ones. Coinfected had higher CD4 cell counts and less likelihood of ART use. In addition, higher frequency of diseases like ichthyosis (22.2 vs. 6.8%), scabies (18.6 vs. 0%), candidiasis (42 vs. 12%), Strongyloidiasis (15.4 vs. 2%) and neurological manifestations like encephalopathy, peripheral neuropathy and HAM/TSP were more frequently reported in coinfected patients. Conclusions HIV-1 and HTLV-1 coinfection and HIV-1 and HTLV-1 /2 triple coinfection were related to shorter survival, higher mortality rate, and faster progression to death, while coinfection by HIV-1/HTLV-2 seems to have neutral association with longer survival, slower AIDS progression, and lower mortality rate. The available evidence indicates an urgent need for prevention and control measures, including screening, diagnosis, and treatment of HIV-1 and HTLV-1/2 coinfected patients. Test-and-treat strategy for patients living with HIV in areas endemic for HTLV infection is mandatory, to avoid the risks of delayed therapy and death for coinfected patients. Systematic Review Registration https://www.crd.york.ac.uk/prospero/, identifier: CRD42021279062.


INTRODUCTION
Human T-cell lymphotropic virus (HTLV) was the first human retrovirus described (1). There are four types of HTLV but only two (HTLV-1 and HTLV-2) are associated with diseases. HTLV-1 is the causative agent of adult T-cell leukemia and tropical spastic paraparesis, while HTLV-2 has been associated with peripheral neuropathy and potentially with tropical spastic paraparesis (2). The human immunodeficiency virus (HIV) causes a progressive depletion of T cells that leads to severe immunodeficiency, increasing the risk of opportunistic infections and malignant neoplasms (3). HIV and HTLV belong to the same family (Retroviridae), share genomic organization, tropism for CD4+ and CD8+ T cells, and routes of infection (sexual, parenteral and vertical). In consequence of common routes of infection, coinfection by both viruses is frequently detected in endemic areas, with higher prevalence in large metropolitan areas (4,5).
HIV-1 and HTLV-1 infect the same cells but have different biological characteristics (6). This can explain why coinfection by these viruses is able to modify the natural history of both infections. In HIV-1coinfection by HTLV-1 differs from that by HTLV-2 in regulating cellular activation of target cells: HTLV-1 promotes a high level of cellular activation, while it is lower in HTLV-2 coinfected subjects. Both viruses promote increase in the frequency of CD4+ cells, but it does not result in an evident benefit to the immune response (4,7).
Some studies have identified that HIV-1 subjects coinfected by HTLV are at higher risk of developing neurological complications, especially HAM/TSP (Human T-lymphotropic virus type-I-associated myelopathy/tropical spastic paraparesis), Adult T-cell leukemia (ATL), neuropathies, opportunistic infections, accelerated progression of HIV, and shorter survival (4,8). On the other hand, some studies support the notion that co-infection by HIV-1 / HTLV-2 does not alter the clinical course of disease, or even that they can promote a protective effect (9)(10)(11). Available studies on coinfection are heterogeneous and fail to identify the factors driving the outcomes observed in this population. The aim of this review is to describe the available findings on clinical and laboratory outcomes in HIV-1 and HTLV-1 or HTLV-2 co-infected individuals since 1995.

MATERIALS AND METHODS
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were followed (12), and our systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO, register number: CRD42021279062).

Eligibility Criteria
Studies considered for inclusion were those with a crosssectional, case-control, or cohort design reporting clinical outcomes: AIDS progression, death, mortality, survival, comorbidities, and opportunistic diseases in a population of HIV-1 and HTLV-1 or HTLV-2 coinfected individuals of all ages, regardless gender, race or ethnicity.

Study Selection and Data Extraction
This review included research articles reporting clinical outcomes in HIV-1 and HTLV-1 or HTLV-2 coinfected individuals. Three reviewers screened the eligible articles in a blinded form using Rayyan tool to read the titles and abstracts, and using the PECO (Population, Exposition, Control and Outcomes) criteria (Table 1), to identify only the studies that met the objectives of the review (13). The studies identified as relevant by title and abstract reading (n = 33) were read in full and 15 studies were eligible for this review. Any divergence between the researchers was resolved by sending the conflicting article to a fourth reviewer, and disagreements were solved by discussion among the reviewers. The elimination of duplicates and the full text read stage were done using the Mendeley reference manager. Evaluation of the methodological quality of the studies was assessed by The Newcastle-Ottawa Scale (NOS) and one version adapted for cross-sectional studies (14).

Included Studies
A total of 326 articles were identified by the search strategy as possibly relevant for the systematic review. After duplicates were removed (n = 2), 324 articles were eligible for title and abstract reading. By using PECO criteria as described in Table 1, were selected 33 articles for full-text reading, 18 of them were excluded. Finally, 15 articles were considered to this systematic review and included 5 case control 6 cross-sectional, and 4 cohort studies as shown in Figure 1.

Quality Assessment
The risk of bias in the study was rated as "low" by using NOS scale and an adaptation for cross sectional studies The mean final scores were 7 (case-control studies), 6 (cross sectional studies), and 6.5 (cohort studies).

HIV/AIDS Related Findings
CD4 cell count was consistently higher in coinfected patients as described also in Table 2 (7,17,23). In addition, one study reported that coinfected patients who died during the studies had higher CD4 T cells count than monoinfected ones 113 vs. 10 cells, (p = 0.023) (18). Survival was shorter for coinfected patients with detectable plasma viremia 6.7 ± 0.9 in comparison to those with undetectable viral load 11.0 ± 0.1 years (p = 0.04) (26

DISCUSSION
The aim of this systematical review was to describe the published information about clinical outcomes in HIV-1 and HTLV-1/HTLV-2 co-infected individuals from 1990 to October 2021. The available studies are controversial, methodologically heterogeneous and fail to identify the factors driving the outcomes observed in HIV-HTLV coinfected population.
Although the present review lacks important information due to design of included studies, we were able to detect some relevant findings associated to coinfection. HTLV-1 mono-infection can cause severe diseases in ∼10% of infected individuals, including adult T-cell leukemia, infective dermatitis and HAM/TSP (27,28). It is also associated with an increase in all-cause mortality, inflammatory and infectious conditions, and other cancers than ATL (27). On the other hand, HTLV-2 mono-infection is probably associated with HAM/TSP like disease, and some bacterial or parasitic infection (28). According to the findings described on this review similar outcomes are detected in HIV-1 / HTLV-1 coinfected patients, as well as in triple coinfection in HIV-1 and HTLV 1/2, resulting in a shorter survival/ higher mortality rates and faster AIDS progression (7,8,15,19,21,23,25,26 , were associated to a higher risk of dying in HIV-1 and HTLV-1 coinfected ones (22). Although HIV-1 and HTLV-2 coinfection has been associated with longer survival, slower AIDS progression, and lower mortality rates (as described in Table 2), the reports describing a potential protective effect of HIV-1 and HTLV-2 coinfection against disease progression found a neutral association, and the available studies have clear limitations, due to the small number of participants, which makes difficult to reach reliable conclusions (11,16,22).
Higher rates of neurological manifestations were found in coinfected individuals, especially the myelopathy (HAM/TSP) related to HIV-1/HTLV-1 coinfection) and peripheral neuropathy (PN, in association with either HIV-1/HTLV-1 or HIV-1/HTLV-2 coinfection). HAM/TSP like manifestations was also described among HIV-1/HTLV-2 coinfection (29). Such findings are compatible with those reported by Zehender, who detected a higher frequency of peripheral neuropathy in HIV-1/HTLV-2 coinfection. Brites also reported cases of encephalopathy among HIV-1 and HTLV 1 co-infected patients, while Mendoza found a higher percentage of HAM/TSP in HIV-1/HTLV-1 co-infected patients (24,25,30). However, we found only a few clinical and neurological studies in coinfection, most of them describing small samples and having a short follow-up.
The rate of HIV disease progression may be affected by many factors, like the infecting viral strain, host susceptibility and immune function, as well as, to exogenous influences such as access to healthcare and presence of coinfections (31,32). Our review shows that AIDS-defining conditions were more frequently seen on coinfected groups (16,19,21,24,25). Some published clinical studies are contradictory when describing the impact of HTLV-1 on AIDS evolution, but most of available evidence suggest that coinfection by HTLV-1 can modify the clinical course of HIV infection and that HIV also can promote a higher risk of HTLV-1 associated diseases (6,9,33,34).
Several reports concluded that HIV/HTLV-1 co-infected patients show an increase in CD4+T cells count in comparison with HIV mono-infected ones, although there is no clear benefit in terms of immune response (7,9,17,23,24,35). It is likely that a rise in dysfunctional CD4+T lymphocytes due to lymphoproliferative effect of HTLV-1 would be responsible for such findings, leading to a false sense of immune competence in HIV co-infected individuals that could cause a delay in starting ART, when therapy initiation is guided by CD4 counts (25). On the other hand, in the coinfection by HTLV-2, the results consistently indicate no modification on the natural course of disease, and even a protective role to AIDS progression (9, 33). HTLV-1 and HIV-1, n = 18 Higher mortality rate among coinfected patients: n = 5, p = 0.01.
Severe forms of scabies are strongly associated with HTLV-1 infection OR: 3.0; 95% CI (1.85-4.86). Crusted form was highly predictive of coinfection (p = 0.01). All deaths were on coinfected, presented with crusted scabies and with a deeper degree of immunodeficiency.

(Continued)
Frontiers in Public Health | www.frontiersin.org This effect may be the result of maintaining normal range levels of CD4 and CD8 counts, lowering HIV replication and immune activation (6). In addition, while HTLV-1 has tropism to CD4+ T cells, HTLV-2 is tropic to CD8+ T cells, which can explain part of the different outcomes observed in HTLV-1 and HTLV-2 infections. Furthermore, it is widely recognized that high viral load is strongly associated with faster progression to AIDS in HIV monoinfected subjects (36). The survival normalization observed in HIV/HTLV-1 coinfected subjects with suppressed plasma viremia, and the predominance of AIDSrelated conditions as a cause of death in coinfected patients indicates that uncontrolled HIV infection is likely to be the main cause of worse prognosis observed in HIV-1 and HTLV-1 coinfected patients. The overestimation of immune status of coinfected patients due to the increase in CD4+ cells could lead, in the past, to a delay in starting ART. However, most of the current clinical guidelines for adults living with HIV AIDS recommend starting ART regardless of CD4 T-cell count (26). The reasons for the observed absence of significant impact of HTLV-2 coinfection on HIV infection are still poorly understood.

LIMITATIONS
This review has some limitations: the findings described by the selected articles were observed in only 5 countries (USA, Italy, Brazil, Mexico and Perú), which limits the generalization to other populations in prevalent regions like, Australia and Japan. Most studies included middle-aged, and only one study was focused on a pediatric population limiting any conclusion related to this age group (23). Finally, we could not perform a direct comparison between studies due to their high methodological heterogeneity.

CONCLUSIONS
HIV-1 and HTLV-1 coinfection and HIV-1 and HTLV-1/2 triple infection are related to lower survival rate, death, and faster progression to death, while coinfection by HIV-1/HTLV-2 seems have neutral associations with higher survival rate, slower AIDS progression, and lower mortality rate. AIDS defining conditions, opportunistic and neurological manifestations were more frequently described on HIV-HTLV-1 coinfected subjects, which indicates AIDS condition as the main cause of death for them. The implementation of test-and-treat strategy for patients living with HIV in areas endemic for HTLV infection is mandatory, to avoid the risks of delayed therapy and death for coinfected patients.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

AUTHOR CONTRIBUTIONS
IM-C, CM, and CS: conception and design of the study, acquisition of data, analysis and interpretation of data, and drafting the article. CB: conception and design of the study, analysis and interpretation of data, drafting the article, and final approval of the version to be submitted. All authors agree to be accountable for the content of the work. All authors contributed to the article and approved the submitted version.

FUNDING
IM-C has a CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) Ph.D. scholarship, finance Code 001. CM has a CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) Ph.D. scholarship, process number: 140187/2021-9. CB is a CNPq researcher, process number: 311095/2020-8. The funder had no role in study design, data collection, data analysis, data interpretation, and writing of the report.