Persistent Low-level Viremia Predicts Subsequent Virologic Failure: Is It Time to Change the Third 90?

Abstract

Background World Health Organization (WHO) guidelines identify human immunodeficiency virus (HIV) viral load <1000 copies/mL as the goal of antiretroviral therapy (ART). However, the clinical implications of viremia below this threshold are unclear in the African context. We examined factors associated with persistent low-level viremia (pLLV) and quantified the risk of subsequent virologic. Methods The African Cohort Study enrolled HIV-infected adults at clinics in Uganda, Kenya, Tanzania, and Nigeria, with assessments every 6 months. We evaluated participants prescribed ART for at least 6 months without virologic failure for pLLV. We used multinomial logistic regression to evaluate associations between prespecified factors of interest and 3 levels of pLLV (<200, 200–499, and 500–999 copies/mL). We used Anderson-Gill extended Cox proportional hazards to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for viremia category associations with time to failure. Results We included 1511 participants with 4382 person-years of follow-up. PLLV <200 copies/mL was observed at 20% of visits while 2% of visits had pLLV 200–499 and 500–999 copies/mL each, with substantial variation by site. Protease inhibitor–containing ART was associated with increased risk of pLLV. Compared to undetectable viral load, pLLV ≥200 copies/mL doubled the risk of developing virologic failure (pLLV 200–499: HR, 1.81 [95% CI, 1.08–3.02]); pLLV 500–999: HR, 2.36 [95% CI, 1.52–3.67]). Conclusions Participants with pLLV ≥200 copies/mL were at increased risk of subsequent virologic failure. Optimized HIV care in this setting should target viral suppression <200 copies/mL.

Factors associated with high-risk low-level viremia leading to virologic failure: 16-year retrospective study of a Chinese antiretroviral therapy cohort

“…Multiple potential factors could explain these differences, including different ART regimens and frequency of testing [6]. However, because of the strict definition of VF used in this study, the occurrence of VF was substantially lower than previous reported data on both resource-rich regions [38,39] and resource-limited regions [2,7]. In a recent study from South Africa, 26% VF according to standard of WHO (VL > 1000 copies/ml once) showed spontaneous control of viral replication without changing treatment regimen, and therefore should not be considered as true VF [2].…”

“…The incidence of VF was calculated by the total number of VF occurrence/total follow-up time * 100% [32,33]. The impacts of LLV on VF were evaluated by the Cox proportional hazards model and the linear mixed-effect model (shown with hazard ratio (HR) and estimate with their 95%CI), in which VL were analyzed as time-varying covariates [7]. The characteristics of high risk LLV that increased the risk of subsequent VF were determined.…”

“…The standards of LLV vary greatly with different guidelines. In resource-limited countries or regions [2,7,8], LLV is defined as a viral load (VL) between 50 and 1000 copies/ ml, according to the World Health Organization (WHO) guidelines [9]. In United States and some other resource-rich countries [10][11][12], LLV is defined as a VL between 50 and 200 copies/ml according to the Department of Health and Human Services (DHHS) guidelines (USA, 2016) [13].…”

“…An earlier national observational cohort study from USA found that an LLV above 400 copies/ml could not predict AIDS or death [17]. However, multiple recent cohort studies worldwide demonstrated that the level of LLV is a determinant of prognosis; high level of LLV (> 200 copies/ml) occurring only once might increase the risk of virologic failure (VF) [7,14,18]. Some studies from developed countries found that persistent LLV or frequently occurring LLV of 50-200 copies/ml also increased the risk of VF [6,19,20].…”

Factors associated with unsuppressed viremia in women living with HIV on lifelong ART in the multi-country US-PEPFAR PROMOTE study: A cross-sectional analysis

“…The vast majority of existing studies have assessed factors associated with viremia >1000 or >400 copies/ml [6,7,10,11]. Emerging antriretroviral drug resistance has been known to occur from levels of 200 copies/ml or above, and use of this threshold eliminates most cases of apparent viremia caused by viral load blips or assay variability [14,15].Therefore this analyses sought to determine clinical and demographic risk factors associated with unsuppressed viremia above 200 copies/ml among a well characterized cohort of women living with HIV originally in the IMPAACT 1077BF/1077FF PROMISE (Promoting Maternal and Infant Survival Everywhere) clinical trial at the time of their entry into the PROMOTE Study. This cohort presents a unique opportunity to assess longer term treatment outcomes among women previously randomized to different antiretroviral (ARV) regimens (WHO option A and option B) during pregnancy and postpartum for the purpose of preventing perinatal HIV transmission [16].…”