Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy

Background In patients infected with human immunodeficiency virus type 1 (H IV-1), combination antiretroviral therapy can result in sustained suppressi on of plasma levels of the virus. However, replication-competent virus can still be recovered from latently infected resting memory CD4 lymphocytes; t his finding raises serious doubts about whether antiviral treatment can era dicate HIV-1. Methods We looked for evidence of residual HIV-1 replication in eight patie nts who began treatment soon after infection and in whom plasma levels of H IV-I RNA were undetectable after two to three years of antiretroviral thera py. We examined whether there had been changes over time in HIV-1 proviral sequences in peripheral-blood mononuclear eel Is, which would indicate resi dual viral replication. We also performed in situ hybridization studies on tissues from one patient to identify cells actively expressing HIV-1 RNA. W e estimated the rate of decrease of latent, replication-competent HIV-1 in resting CD4 lymphocytes on the basis of the decrease in the numbers of prov iral sequences identified during primary infection and direct sequential me asurements of the size of the latent reservoir. Results Six of the eight patients had no significant variations in proviral sequences during treatment. However, in two patients there was sequence ev olution but no evidence of drug-resistant viral genotypes. In one patient, extensive in situ studies provided additional evidence of persistent viral replication in lymphoid tissues. Using two independent approaches, we estim ated that the half-life of the latent, replication-competent virus in resti ng CD4 lymphocytes was approximately six months. Conclusions These findings suggest that combination antiretroviral regimens suppress HIV-1 replication in some but not all patients. Given the half-li fe of latently infected CD4 lymphocytes of about six months, it may require many years of effective antiretroviral treatment to eliminate this reservo ir of HIV-1. (N Engl J Med 1999;340:1605-13.) (C) 1999, Massachusetts Medic al Society.