Prolonged retention of drug resistance mutations and rapid disease progression in the absence of therapy after primary HIV infection

We report two separate, unrelated instances of the transmission of HIV-containing mutations associated with high levels of resistance to protease inhibitors or reverse transcriptase inhibitors. In the absence of antiretroviral drugs, these mutations persisted almost unchanged in the newly infected index cases, whereas most mutations reverted to wild type in the source patients upon discontinuation of therapy. Furthermore, a rapid loss of CD4 cells was observed in the newly infected individuals. In a setting with a low prevalence of primary HIV drug resistance, we recently observed two cases of the transmission of drug-resistant, highly fit strains of HIV. In both events, phylogenetic analysis confirmed a close relationship between the source and index cases in the HIV pol, gag, and env genes (data not shown). Source case 1 was a patient with extensive antiretroviral experience, having been treated with zidovudine, zalcitabine, lamivudine, stavudine, saquinavir and indinavir in various combinations before April 1998. Under therapy, the plasma viral load ranged between 14 000 and 230 000 copies/ml, and the CD4 cell count ranged between 70 and 200 cells/mm3. Genotypic analysis of plasma HIV-RNA isolates from samples collected between December 1996 and April 1998 (the date closest to the serodiagnosis of HIV infection in index case 1; Table 1) was consistent with broad resistance to protease inhibitors and nucleoside analogues. Of interest was the fact that the source case stopped all antiretroviral drugs in March 1998 and the predominant plasma virus reverted to wild type within 7 months.Table 1: Resistance-mutations, antiretroviral treatment, and viral load/CD4 cell counts of source and index cases 1 and 2.Index case 1 was a patient who shared injections with source case 1, who tested repeatedly HIV seronegative from July 1992 to August 1995. In June 1998, HIV-1 infection was diagnosed by Western blot confirmation of HIV-1-specific enzyme-linked immunosorbent assay. In a July 1998 plasma sample, genotypic testing of the HIV-RNA isolate revealed resistance-associated mutations in HIV protease and reverse transcriptase (RT) similar to those of source case 1. The plasma viral load increased from approximately 10 000 HIV-RNA copies/ml in 1998 to more than 100 000 copies/ml by early 2001. The predominant plasma HIV genotype was remarkably stable over this time period, with no change in protease-related mutations. In the RT region, the 184V mutation was lost on the predominant strain, whereas the 215Y mutation partly reverted to 215C. The genotype otherwise showed no significant change. The 44D and 75M mutations tended to persist as mixtures. Index patient 1 claimed no use of antiretroviral drugs during this period. This was supported by at least two lines of evidence: (i) the patient was not enrolled in the BC Centre for Excellence in HIV/AIDS Drug Treatment Program, the source of free antiretroviral drugs to all enrolled HIV-infected individuals in British Columbia, Canada; (ii) plasma levels of protease inhibitors and non-nucleoside analogues in all samples were undetectable by high-performance liquid chromatography/tandem mass spectrometry. In the second instance of transmission, the predominant viral mutations of source case 2 developed after therapy with zidovudine, lamivudine and nevirapine between May 1996 and May 1999 (Table 1). Therapy was discontinued in May 1999, and all resistance-associated mutations gradually reverted in the ensuing 2 years, except G190A. Index case 2, the source case's sexual partner, experienced a mononucleosis-like syndrome consistent with primary HIV infection in January 2001, and was HIV seropositive by enzyme-linked immunosorbent assay and Western blot. Genotypic analysis of plasma HIV-RNA isolates from January to July 2001 identified a similar genotype to that seen in the later samples from source case 2, with a persistent G190A mutation in RT. Index case 2 had a rapid decline in CD4 cells during the next 6 months of follow-up. The viral evolution in the two index cases is remarkable for the prolonged retention of mutations in the absence of therapy for up to 3 years. This contrasts with the rapid reversion in source case 1 after the interruption of therapy, and the more gradual reversion of most resistance-associated mutations in source case 2. After transmission, the genotype containing the G190A mutation persisted in index case 2 to 6 months of follow-up. However, as therapy was restarted shortly after transmission in source case 2, comparison cannot be made for similarities in viral evolution. In both index cases, the sustained elevated viral loads and rapid decreases in CD4 cells indicate a high level of replicative fitness and pathogenicity of these drug-resistant viruses. However, because of a relatively short follow-up period (6 months), the rapid disease progression in index case 2 could have been caused by an exaggerated but temporary immune suppression related to primary HIV infection. This would not be an adequate explanation for index case 1, in which there was a follow-up period of 3 years. In the virus transmitted from source to index case 1, there was a positively charged amino acid at position 320 of the V3 region suggestive of a syncytium-inducing phenotype that might help rationalize the rapid disease progression [1]. Mutations at the gag proteolytic cleavage site were also identified in all four cases, which might enhance the replicative capacity of mutant viruses and adversely affect disease progression [2,3]. It is interesting in these cases that whereas the same HIV genotype persists in the newly infected individual, it is overgrown by wild type in the source patient. It is likely that a pre-existing reservoir of HIV quasispecies helps expedite the re-establishment of wild-type virus [4]. Alternatively, the genotypic assays may have failed to detect the ‘historical’ persistent species that have since become minority species. As therapy is resumed, the resistant species will rapidly emerge as dominant [5,6]. In contrast, both conditions will be lacking in the setting of new infection. In the absence of drugs, a resistant genotype will normally require multiple revertant mutations to generate the wild-type virus. If the infecting strain already possesses a high degree of replicative fitness, such mutations will take a much longer period of time. This first documentation of HIV cases in which the same drug-resistant genotype persists for prolonged periods of time after primary infection suggests that resistance testing should be considered before treatment in the chronically infected and treatment-naive patient. This is especially true if it is suspected that the infection has been acquired from a source previously on treatment, even if not shortly after seroconversion.

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