HIV-1 persistent viremia is frequently followed by episodes of low-level viremia

Abstract

After the start of antiretroviral therapy (ART), plasma HIV-RNA levels should fall below the limit of detection (LOD) within 24 weeks. Hence, the prolonged decline of HIV-RNA after ART initiation is defined as persistent viremia (PV). In this retrospective study, we analyzed factors associated with PV. Next-generation sequencing of viral RNA/DNA was performed to study viral evolution and the emergence of drug-resistance mutations in HIV-infected patients with PV (n = 20). In addition, HIV-DNA species, immunological parameters, and clinical data of the patients were analyzed. We found that the possible causes for PV were divers, and both virologic and host parameters of this particular cohort were heterogeneous. We identified viruses with therapy-associated DRMs in six patients (30%); two of these were detected as minority variants. Five patients had sub-optimal drug levels (25%) and the baseline plasma viral loads were relatively high. Strikingly, we observed that >40% of the PV patients finally reaching HIV levels below the LOD later on showed up with episodes of low-level viremia (LLV). However, the amount of PBMC derived HIV-DNA species was not correlated with the likelihood of LLV after PV. According to our data, we conclude that drug-resistant viruses, sub-optimal drug level, and high baseline viral loads might be probable reasons for the prolonged RNA decline only in a sub-set of patients. In the absence of emerging DRMs and/or compliance issues, the clinical implications of PV remain unclear; however, PV appears to be a risk factor for episodes of LLV.

Keywords: Antiretroviral therapy; Drug resistance; HIV-1; Low-level viremia (LLV); Persistent viremia (PV); Prolonged decline.

Fig. 1

Duration of PV in patients with and without therapy switch: Median (IQR) of decline periods between genotyping and first pVL < LOD of patients with (+TS) and without treatment switch (−TS) after genotyping. Patients who were switched due to DRMs were excluded from this analysis. Significance was tested using two-tailed Mann–Whitney test

Fig. 2

Persistent Viremia is often followed by LLV. a Follow-up events (no events, transient HIV-1 RNA blips, showing up with episodes of low-level viremia) of patients who received a first-line therapy and who reached pVL <50 RNA copies/ml were depicted (left). Sub-analysis of patients reaching pVL <50 who had low drug levels as well drug-resistant viruses (middle) and those who had not (right). b Total HIV-1 DNA, integrated proviral DNA, and non-integrated viral DNA (2-LTR circles) were determined using DNA isolated from PBMCs collected at time point of genotyping. The lines indicate mean values

Fig. 3

Course of viral load decline and treatment regimens. Viral load declines and treatment regimens of first-line treated patients PV-1–PV-14 and therapy-experienced patients (PV-15–PV-20) are depicted. The courses of pVL and treatment regimens are illustrated for each patient. DRM drug-resistance mutation, LD low drug level, LF lost to follow up before reaching pVL <50