Persistence of transmitted drug resistance among subjects with primary human immunodeficiency virus infection

Abstract

Following interruption of antiretroviral therapy among individuals with acquired drug resistance, preexisting drug-sensitive virus emerges relatively rapidly. In contrast, wild-type virus is not archived in individuals infected with drug-resistant human immunodeficiency virus (HIV) and thus cannot emerge rapidly in the absence of selective drug pressure. Fourteen recently HIV-infected patients with transmitted drug-resistant virus were followed for a median of 2.1 years after the estimated date of infection (EDI) without receiving antiretroviral therapy. HIV drug resistance and pol replication capacity (RC) in longitudinal plasma samples were assayed. Resistance mutations were characterized as pure populations or mixtures. The mean time to first detection of a mixture of wild-type and drug-resistant viruses was 96 weeks (1.8 years) (95% confidence interval, 48 to 192 weeks) after the EDI. The median time to loss of detectable drug resistance using population-based assays ranged from 4.1 years (conservative estimate) to longer than the lifetime of the individual (less conservative estimate). The transmission of drug-resistant virus was not associated with virus with reduced RC. Sexual transmission of HIV selects for highly fit drug-resistant variants that persist for years. The prolonged persistence of transmitted drug resistance strongly supports the routine use of HIV resistance genotyping for all newly diagnosed individuals.

FIG. 1.

(a) Kaplan-Meier plot of the time to first detection of the WT virus as a mixture (WT/DR) in the population. (b) Kaplan-Meier plot of the time to complete replacement (i.e., last detection of any DR virus). Dashed lines indicate upper and lower 95% CIs.

FIG. 2.

Longitudinal FC susceptibility results for a representative drug for each subject. Red circles indicate EFV susceptibility. Blue circles indicate lopinavir susceptibility. Subject 01-0629, infected with a K103K/N mixture at baseline, did not show reduced EFV susceptibility at baseline or during follow-up. Subject 01-0180 showed a waning of reduced EFV susceptibility over time.

FIG. 3.

Estimation of the relative fitness advantage of WT virus over virus harboring K103N in patient 01-0180. (a) FC in susceptibility to EFV over time (points) and the fit of a model that assumes a log-linear relationship between FC and frequency of the WT variant (see Materials and Methods). (b) Relationship between the time during which a mixture persists and the selective advantage of WT.

FIG. 4.

Dynamics of RC and FC in susceptibility to EFV in patient 01-0180. Despite a dramatic drop in FC, the RC remains relatively stable over the period of observation.

FIG. 5.

Box plots showing the median RC among eight different groups, with 25th and 75th percentiles shown by the box and the complete range indicated by whiskers. PDR14, study patients with transmitted DR virus; PDR33, 33 primary infection patients infected with DR virus but not included in present study due to antiretroviral treatment choices after entry; PWT141, 141 primary patients infected with WT virus; WT962, unrelated WT samples with infection of undetermined duration (n = 962); NNRTI-1, samples with an isolated single NNRTI major drug resistance mutation (n = 1,522); NNRTI-2, samples with only two major NNRTI drug resistance mutation (n = 236); PI-R, samples with ≥1 major PI mutation (no NRTI or NNRTI mutations) (n = 459); and PI_NRTI-R, samples with ≥1 major PI mutation and ≥1 major NRTI mutation (without NNRTI mutations).

FIG. 6.

The total number of nonsynonymous mutations in predicted CTL epitopes between the baseline sequence and subsequent sequences was determined for all study participants over time. Overall, there is a large variation in the number of substitutions in each individual subject, though the mean number (represented by the solid line) shows an increase over time, demonstrating that viral evolution is ongoing despite the persistence of drug resistance mutations.

FIG. 7.

Schematic illustration of the first decade (approximately) of HIV infection following infection with a resistant strain of virus. Patients initially infected with a DR variant will typically demonstrate a transient high-titer viremia, followed by a spontaneous decline to a steady-state or “set point” viremia. During these first 6 months, bulk sequencing of plasma virus will typically detect only resistant virus in patients with transmitted DR virus. Years may pass during which the gradual process of random and potentially selective mutations results in the appearance of a mixture at the site(s) of a previous drug-resistant mutation(s) followed by ultimate “reversion” or, more accurately, replacement by WT virus. The resistant variant, however, will persist for the life of the patient, harbored within the reservoir of long-lived memory CD4 cells. ARV, antiretroviral.