HIV type 1 (HIV-1) drug resistance mutations were selected during antiretroviral therapy successfully suppressing plasma HIV-1 RNA to <50 copies͞ml. New resistant mutant subpopulations were identified by clonal sequencing analyses of viruses cultured from blood cells. Drug susceptibility tests showed that biological clones of virus with the mutations acquired during successful therapy had increased resistance. Each of the five subjects with new resistant mutants had evidence of some residual virus replication during highly active antiretroviral therapy (HAART), based on transient episodes of plasma HIV-1 RNA > 50 copies͞ml and virus env gene sequence changes. Each had received a suboptimal regimen before starting HAART. Antiretroviral-resistant HIV-1 can be selected from residual virus replication during HAART in the absence of sustained rebound of plasma HIV-1 RNA.

Changes in human immunodeficiency virus (HIV) type 1 concentration and protease genotype were evaluated in semen specimens from 22 HIV-positive men before and 6 months after the addition of indinavir to dual nucleoside therapy. Seminal HIV was detected by polymerase chain reaction analysis for DNA or RNA for 59% of men before combination treatment and persisted at 6 months for 31% of the men who initially had seminal HIV detected (P = .026). The maximum levels of cell-free RNA, cell-associated RNA, and proviral DNA in semen before treatment and at 6 months were 400,000 and 10,000 copies/mL, 70,000 and 27,000 copies/mL, and 80,000 and 3,000 copies/mL, respectively. Three of the four men with persistent seminal DNA had plasma viral loads of > 10,000 copies/mL before treatment. One patient who became intolerant to indinavir had seminal HIV RNA detected by PCR analysis after 6 months. Although none of the cultures of semen specimens from the four men with PCR analysis-detectable seminal DNA after 6 months yielded HIV, indinavir resistance mutations were identified in a seminal leukocyte DNA specimen from one patient, and a second patient whose therapy was switched to saquinavir had different protease inhibitor resistance mutations in seminal and blood leukocyte DNA specimens. HIV-1 protease inhibitor resistance mutants may emerge in the semen of patients receiving combination therapy.