HIV and HTLV-1 Coinfection: The Need to Initiate Antiretroviral Therapy

According to the latest Department of Health and Human Services guidelines for the use of antiretroviral therapy (ART) in HIV-1-infected persons, initiation of ART is recommended for all HIV-infected persons regardless of the CD4 count. In resource-limited settings where ART is not available for all patients, treatment should be prioritized for those with the following conditions: pregnancy, CD4 count <200 cells/mm³ or AIDS-defining illness, HIV-associated nephropathy, HIV-associated dementia, hepatitis B virus coinfection, and acute HIV infection. ¹ We suggest that coinfection with human T-cell lymphotropic virus type 1 (HTLV-1) should be added to this prioritized list for the following reasons:

The predictive value of CD4 count as a marker of HIV-related immunosuppression and disease stage for persons coinfected with HIV and HTLV-1 is likely not the same as for persons infected with HIV alone. Human T-cell lymphotropic virus type 1 promotes the clonal expansion of CD4-infected T lymphocytes, causing an artificially elevated CD4 count in coinfected persons. ² Compared to HIV-infected patients with CD4 counts greater than 200 cells/mm³, HIV/HTLV-1-coinfected individuals with similar CD4 counts are at increased risk for developing opportunistic infections. ^3,4 Thus, a high CD4 count in coinfected persons does not necessarily reflect a competent immune system.

HIV/HTLV-1 coinfection is associated with accelerated progression to AIDS and worse outcomes of HIV-related opportunistic infections. ^{5 –7} Human T-cell lymphotropic virus type 1 induces HIV viral replication and the transition from M- to T-tropic HIV phenotype, which is often a marker of HIV disease progression. ⁸ In addition, compared to individuals infected with only HIV, HIV/HTLV-1-coinfected individuals have higher production of proinflammatory cytokines, most notably interleukin 2 and interferon-γ, suggesting that metabolic and cardiovascular complications mediated by chronic immune activation could be more pronounced among coinfected individuals. ⁹

In countries with a high burden of tuberculosis, tuberculosis is more common in persons infected with both HIV and HTLV-1. ¹⁰ The risk of tuberculosis is about 2.5-fold higher in HIV/HTLV-1-coinfected patients compared to patients with HIV infection alone, and both morbidity and mortality are higher in patients with HIV/HTLV-1 coinfection. ^11,12

Using quantitative HTLV-1 proviral load (PVL) as an indicator of when to initiate ART in asymptomatic HIV/HTLV-1-coinfected individuals with preserved CD4 counts is often impractical due to limited laboratory capacity in countries where HTLV-1 infection is endemic. In addition, HTLV-1 PVL varies widely in asymptomatic carriers and in persons with HTLV-associated disease ¹³ ; and the relationship between HTLV-1 PVL and HIV-associated manifestations in HIV/HTLV-1-coinfection has not been well established. Hence, neither quantitative HTLV-1 PVL nor CD4 count is a clinically useful indicator of disease or immune status in the setting of HIV/HTLV-1 coinfection.

In contrast, limited evidence suggests that coinfection with HTLV-2, common among HIV-infected injection drug users in the United States and Europe, has a protective effect against progression of HIV infection to AIDS. ¹⁴ Human T-cell lymphotropic virus type 2 has been associated with increased CCL3L1 expression, a chemokine that inhibits HIV-1 cell entry by binding to CCR5. ⁶ Furthermore, HIV/HTLV-2-coinfection has been linked to a “long-term nonprogressor” phenotype. Therefore, the effect of HTLV-1 and HTLV-2 coinfection upon HIV infection may be different, and our recommendation for considering earlier initiation of ART in persons with HIV/HTLV-1 coinfection may not apply to people with HIV/HTLV-2 coinfection.

In conclusion, compared to a CD4 count greater than 200 cells/mm³ in persons infected with HIV alone, a similar CD4 count in persons coinfected with HIV and HTLV-1 may mask immunosuppression, and if used as an indicator for determining when to initiate ART in resource-limited settings, may delay initiation of ART, resulting in a missed opportunity to slow the progression to AIDS, decrease the risk of tuberculosis, and lessen complications related to chronic immune activation. Therefore, initiating ART earlier in HIV/HTLV-1-coinfected persons, independent of CD4 count, should be considered, especially in areas where tuberculosis is endemic.