Assessing the impact of adherence to anti-retroviral therapy on treatment failure and resistance evolution in HIV

Abstract

The adherence of patients to therapy is a crucial factor for successful HIV anti-retroviral therapy. Imperfect adherence may lead to treatment failure, which can cause the emergence of resistance within viral populations. We have developed a stochastic model that incorporates compartments of latently infected cells and virus genotypes with different susceptibilities to three simultaneously used drugs. With this model, we study the impact of several key parameters on the probability of treatment failure, i.e. insufficient viral suppression, and the emergence of resistance. Specifically, we consider the impact of drug dosage, drug half-lives, fitness costs for resistance, different basic reproductive numbers of the virus and the influence of pre-existing mutations under various levels of adherence. Furthermore, we also investigate the influence of different temporal distributions of non-adherent days (drug holidays) during a treatment. Factors that promote resistance evolution include a high reproductive number, extended drug holidays and poor adherence. Pre-existing mutations only have a substantial effect if they confer resistance against more than one drug. Overall, our study highlights the importance of the interactions between imperfect adherence, pharmacodynamics, pharmacokinetics and latently infected cells for our understanding of drug resistance and therapy failure in HIV anti-retroviral therapy.

Estimation of the HIV-1 backward mutation rate from transmitted drug-resistant strains

“…This is in agreement to previous modeling work (Cadosh et al., 2012, Pearson et al., 2011, Ribeiro and Bonhoeffer, 2000). However, the effective population size for stochastic within-host models of HIV is still debated (Kouyos et al., 2006).…”

“…Our choice of initial conditions is similar to values used in previous literature (Cadosh et al., 2012). To study the effect of one of these initial conditions we performed a sensitivity analysis on the inoculum size $V_r\left(0\right)$.…”

“…The virus–cell dynamics are simulated effectively in a volume of 1 ml, as in previous studies (Cadosh et al., 2012, Pearson et al., 2011, Ribeiro and Bonhoeffer, 2000). In a volume of 1 ml of blood, the target population size was taken as 10 4 cells.…”

Factors Associated with First-Line Antiretroviral Therapy Failure amongst HIV-Infected African Patients: A Case-Control Study

“…In the sub-Saharan Africa, many patients who experience virological failure do not switch to potent second line regimens due to resource limitation, yet those who remain on a failing first-line regimen experience disproportionately higher morbidity and mortality compared to those who switch [6,7]. Documented factors associated with virological treatment failure include poor adherence, certain ART regimen combinations, primary infection with drug resistant strains of HIV, prior exposure to antiretroviral monotherapy, high baseline plasma viral load and low baseline CD4 count [8][9][10][11].…”

Factors for nonadherence to first line art therapy in a cohort of Human Immunodeficiency Virus positive adult patients

“…high pre-treatment viral load, low pre-treatment CD4 count, prior WHO stage), drug interactions, side effects, drug toxicity or poor adherence to treatment, few drug regimens, primary infection with drug-resistant strains of HIV. [12][13][14][15][16] Study aimed at identifying the reasons for switch over of first line ART regimen to second line and to determine the reasons for discontinuation of 1st line ART in a cohort of HIV positive adult patients enrolled at ART Centre, Victoria Hospital, Bengaluru, Karnataka, India.…”