Efavirenz Therapy in Rhesus Macaques Infected with a Chimera of Simian Immunodeficiency Virus Containing Reverse Transcriptase from Human Immunodeficiency Virus Type 1

Abstract

The specificity of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for the RT of human immunodeficiency virus type 1 (HIV-1) has prevented the use of simian immunodeficiency virus (SIV) in the study of NNRTIs and NNRTI-based highly active antiretroviral therapy. However, a SIV-HIV-1 chimera (RT-SHIV), in which the RT from SIVmac239 was replaced with the RT-encoding region from HIV-1, is susceptible to NNRTIs and is infectious to rhesus macaques. We have evaluated the antiviral activity of efavirenz against RT-SHIV and the emergence of efavirenz-resistant mutants in vitro and in vivo. RT-SHIV was susceptible to efavirenz with a mean effective concentration of 5.9 ؎ 4.5 nM, and RT-SHIV variants selected with efavirenz in cell culture displayed 600-fold-reduced susceptibility. The efavirenz-resistant mutants of RT-SHIV had mutations in RT similar to those of HIV-1 variants that were selected under similar conditions. Efavirenz monotherapy of RT-SHIV-infected macaques produced a 1.82-log-unit decrease in plasma viral-RNA levels after 1 week. The virus load rebounded within 3 weeks in one treated animal and more slowly in a second animal. Virus isolated from these two animals contained the K103N and Y188C or Y188L mutations. The RT-SHIV-rhesus macaque model may prove useful for studies of antiretroviral drug combinations that include efavirenz.

A Mathematical Model to Predict HIV Virological Failure and Elucidate the Role of Lymph Node Drug Penetration

“…For efavirenz monotherapy, a majority of virtual patients having a general level of adherence of 20% or more had virological failure with resistance at the end of 48 weeks. In comparison, two out of three macaques having plasma drug concentrations similar to those of simulated patients had high viral loads and significant resistance within the first 42 weeks of therapy 5. For the treatment combination, predictions of virological failure (green bars) are displayed along a regression curve that is based on clinical data 9.…”

“…This choice was driven by the availability of virological failure data5, 9, 10 and the required parameters for the model (lymph node drug penetration,8 see below).…”

“…The model successfully shows how the relationship between drug intake and virological outcomes varies for different drugs. Unfortunately, the model falls short of explaining issues such as the lack of efficacy of efavirenz monotherapy: it foretells an absence of virological failure for patients having moderate or high drug adherence, despite clinical expectations and in vivo evidence 5. We took this discrepancy as a learning opportunity, and revisited this mathematical model.…”

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS

“…Similar studies have been performed in pigtail macaques utilizing RT-SHIVmne, which contains HIV-1 RT in the genetic background of SIVmne, a pathogenic isolate from the lymph node of an infected pigtail macaque [140]. Importantly, plasma virus isolates from macaques infected with either RT-SHIVHXB2 or RT-SHIVmne, and treated with NRTIs/NNRTIs, contained genetic mutations known to confer drug resistance such as K65R (tenofovir), V108I (efavirenz,) and K103N and M184I (emtricitabine), making these chimeras useful tools for the preclinical evaluation of in vivo drug resistance [140][141][142][143].…”

Use of Animal Models for Anti-HIV Drug Development

“…Efavirenz monotherapy leads to the emergence of common resistance mutations that are seen in patients (Ambrose et al, 2007;Hofman et al, 2004). Efavirenz combined with tenofovir and FTC is a commonly prescribed combination therapy for HIV-infected individuals and was shown to be effective in reducing RT-SHIV plasma viremia in two species of macaques (Ambrose et al, 2007;North et al, 2005).…”