Increased Rate of CD4+ T-Cell Decline and Faster Time to Antiretroviral Therapy in HIV-1 Subtype CRF01_AE Infected Seroconverters in Singapore

Abstract

BackgroundIt remains controversial as to whether HIV-1 subtypes influence disease progression. Singapore offers a unique opportunity to address this issue due to the presence of co-circulating subtypes. We compared subtype CRF01_AE and non-CRF01_AE infected patients, with regards to estimated annual rate of CD4+ T-cell loss and time from estimated data of seroconversion (EDS) to antiretroviral therapy (ART).MethodsWe recruited ART-naive patients with known dates of seroconversion between October 2002 and December 2007 at the Singapore Communicable Disease Centre, the national reference treatment centre. Multilevel mixed-effects models were used to analyse the rate of CD4+ T-cell decline. Time from EDS to ART was analyzed with the Kaplan-Meier survival method and compared with Cox proportional hazards models.Results54 patients with previously assigned HIV-1 subtypes (24 CRF01_AE, 17 B, 8 B', 1 CRF33_01B, 3 CRF34_01B and 1 G) were observed for 89 patient-years. Subtype CRF01_AE and non-CRF01_AE infected patients did not differ in age, gender, risk factor, rate of symptomatic seroconversion, baseline CD4+ T-cell count, log10 viral load or haemoglobin concentration. The estimated annual rate of CD4+ T-cell loss was 58 cells/mm3/year (95% CI: 7 to 109; P = 0.027) greater in subtype CRF01_AE infected patients compared to non-CRF01_AE patients, after adjusting for age, baseline CD4+ T-cell count and baseline log10 viral load. The median time from EDS to ART was 1.8 years faster comparing CRF01_AE to non-CRF01_AE infected patient with a 2.5 times (95% CI: 1.2-5.0; P = 0.013) higher hazard for ART initiation, after controlling for age, baseline CD4+ T-cell count and baseline log10 viral load.ConclusionsInfecting subtype significantly impacted the rate of CD4+ T-cell loss and time to treatment in this cohort. Studies to understand the biological basis for this difference could further our understanding of HIV pathogenesis.

The effects of HIV-1 subtype and ethnicity on the rate of CD4 cell count decline in patients naive to antiretroviral therapy: a Canadian-European collaborative retrospective cohort study

“…24 Our analysis was restricted to adults (age ≥ 16 yr) enrolled in the studies between January 1998 and June 2010 with a known HIV-1 subtype and at least 2 CD4 cell count measurements within 1 year while they were naive to antiretroviral therapy. We selected CD4 cell count measurements in patients 16,17,25,26 In this study, we omitted any patient with a first AIDS event either before or within 3 months after their first CD4 cell count measurement; these patients were likely to be late presenters. To avoid including CD4 cell count measurements made during acute infection, we removed measurements within 6 months of documented seroconversion (known only for 15% of patients) and measurements < 100 cells/mL at the beginning of a series; these measurements may reflect the rapid CD4 cell count decline that occurs immediately after seroconversion before the immune system responds to infection.…”

HIV gp120 H375 Is Unique to HIV-1 Subtype CRF01_AE and Confers Strong Resistance to the Entry Inhibitor BMS-599793, a Candidate Microbicide Drug

“…Recombination among HIV-1 subtypes occurs frequently, resulting in genetic mosaics termed circulating recombinant forms (CRFs), whereby the two globally predominant CRFs are CRF01_AE and CRF02_AG (23). Interestingly, individuals infected with CRF01_AE HIV-1 can progress to disease faster than those infected with other HIV-1 subtypes or CRFs (52), yet the mechanism(s) responsible for this phenomenon remains unknown. Drug efficacy may also vary according to subtype classification (20,27).…”

HIV-1 subtype CRF01_AE and B differ in utilization of low levels of CCR5, Maraviroc susceptibility and potential N-glycosylation sites

“…Subtype differences have been shown to influence CD4 decline rates, (Touloumi et al, 2013) leading to faster time to anti-retroviral therapy (Ng et al, 2011a). However, the reason behind these differences remains unknown.…”

“…The differential rate of progression in this population correlates with viral subtype, with AE showing faster progression than B subtype (Ng et al, 2011a). We characterized the Envs for infectivity in cells expressing different levels of CCR5, pattern of potential N-linked glycosylation sites (PNGS) and MVC resistance profile along with other correlative analyses.…”

“…Studies have shown that HIV subtypes vary in terms of plasma viral load (Kivela et al, 2005); rate of CD4+ T cell decline (Easterbrook et al, 2010; Ng et al, 2011a), prevalence of CXCR4 tropism (Ng et al, 2013), enhanced biological fitness including replicative advantage (Lau et al, 2010; Njai et al, 2006), increased virulence and pathogenicity (Hemelaar, 2013), and accumulation of anti-retroviral resistance mutations (Tang and Shafer, 2012). Moreover, studies have also documented differences in CD4 recovery after initiation of anti-retroviral therapy in patients infected with AE versus B subtype (Chow et al, 2015; Oyomopito et al, 2013).…”