Virus-specific T-helper cells are considered critical for the control of chronic viral infections. Successful treatment of acute HIV-1 infection leads to augmentation of these responses, but whether this enhances immune control has not been determined. We administered one or two supervised treatment interruptions to eight subjects with treated acute infection, with the plan to restart therapy if viral load exceeded 5,000 copies of HIV-1 RNA per millilitre of plasma (the level at which therapy has been typically recommended) for three consecutive weeks, or 50,000 RNA copies per ml at one time. Here we show that, despite rebound in viraemia, all subjects were able to achieve at least a transient steady state off therapy with viral load below 5,000 RNA copies per ml. At present, five out of eight subjects remain off therapy with viral loads of less than 500 RNA copies per ml plasma after a median 6.5 months (range 5-8.7 months). We observed increased virus-specific cytotoxic T lymphocytes and maintained T-helper-cell responses in all. Our data indicate that functional immune responses can be augmented in a chronic viral infection, and provide rationale for immunotherapy in HIV-1 infection.
New information about the benefits and limitations of testing for resistance to human immunodeficiency virus (HIV) type 1 (HIV-1) drugs has emerged. The International AIDS Society-USA convened a panel of physicians and scientists with expertise in antiretroviral drug management, HIV-1 drug resistance, and patient care to provide updated recommendations for HIV-1 resistance testing. Published data and presentations at scientific conferences, as well as strength of the evidence, were considered. Properly used resistance testing can improve virological outcome among HIV-infected individuals. Resistance testing is recommended in cases of acute or recent HIV infection, for certain patients who have been infected as long as 2 years or more prior to initiating therapy, in cases of antiretroviral failure, and during pregnancy. Limitations of resistance testing remain, and more study is needed to refine optimal use and interpretation.
BACKGROUND-It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens.
Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.
Based on the samples that could be amplified, low-level viremia in children and adults receiving HAART with prolonged suppression of viremia to less than 50 copies/mL of HIV-1 RNA may result primarily from archival, pre-HAART virus, reflecting earlier treatment conditions, and does not appear to require development of new, HAART-selected mutations reflecting partial resistance to therapy. Low-level viremia below 50 copies/mL may represent less of a concern regarding impending drug failure of current HAART regimens. However, the archival drug-resistant virus may be relevant regarding future treatment strategies.
Background
The clinical relevance of detecting minority drug-resistant HIV-1 variants is uncertain.
Methods
To determine the effect of pre-existing minority non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant variants on the risk of virologic failure (VF), we reanalyzed a case-cohort substudy of efavirenz recipients in ACTG A5095. Minority K103N or Y181C populations were determined by allele-specific PCR (ASPCR) in subjects without NNRTI resistance by population sequencing. Weighted Cox proportional hazards models adjusted for recent adherence estimated the relative risk of VF in the presence of NNRTI-resistant minority variants.
Results
The evaluable case-cohort sample included 195 subjects from the randomly selected subcohort (51 with VF, 144 without failure [NF]), plus 127 of the remaining subjects with VF. Presence of minority K103N or Y181C mutations, or both, was detected in 8 (4.4%), 54 (29.5%) and 11 (6%), respectively, of 183 evaluable subjects in the random subcohort. Detection of minority Y181C mutants was associated with an increased risk of VF in the setting of recent adherence (HR=3.45, CI=1.90, 6.26), but not in non-adherent subjects (HR=1.39, CI=0.58, 3.29). Of note, 70% of subjects with minority Y181C achieved long-term viral suppression.
Conclusions
In adherent patients, pre-existing minority Y181C mutants more than tripled the risk of VF of first-line efavirenz-based ART.
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