ArticlesTransmission of antiretroviral-drug-resistant HIV-1 variants
Introduction
Resistance of HIV-1 to antiretroviral drugs is a widespread problem that limits the efficacy of antiretroviral treatment. The main causes for the emergence of drug-resistant HIV-1 variants include suboptimum treatment or incomplete adherence to therapy.1 Other causes are related to the pre-existence of drug-resistant variants within HIV-1 quasispecies2, 3 and the transmission of HIV-1-resistant variants at the time of the infection.4, 7
In more-developed countries, most HIV-1-infected patients are treated with combined antiretroviral therapy that includes reverse-transcriptase inhibitors (RTIs) and protease inhibitors. Patients with successive virological failure to initial and rescue therapy harbour HIV-1 variants that have mutations associated with resistance to several antiretroviral drugs, which limits the success of subsequent therapy.8, 9 This fact has led to the concept that an initial treatment able to fully suppress viral replication provides the best chance for the patient in the long term. Triple therapy has been associated with a better virological and clinical outcome than double therapy.10, 11 Consequently, the transmission of drug-resistant HIV-1 variants will decrease the efficacy of initial therapy by impairing the activity of one or more drugs included in the treatment regimen.
Over the past 5 years, in countries with wide access to antiretroviral drugs, the transmission of HIV-1 variants resistant to zidovudine has been detected in 5–15% of individuals,4, 5 and transmission of variants resistant to lamivudine and nevirapine has been also reported.6, 12 The transmission of HIV-1 variants resistant to RTI and protease inhibitors has been reported in one patient with primary HIV-1 infection.7 However, there have been no systematic studies of the transmission of HIV-1 variants resistant to protease inhibitors.
We assessed the prevalence of drug-resistant HIV-1 variants in individuals with documented primary HIV-1 infection.
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Study participants
All consecutive individuals with primary HIV-1 infection referred to the Geneva AIDS Centre between January, 1996, and July, 1998 were included. Biological characteristics of primary HIV-1 infection were defined as negative antibodies to HIV-1 with detectable p24 antigen or HIV-1 RNA, or positive antibodies to HIV-1 with an incomplete western blot, or a positive western blot with acute retroviral syndrome13 and an identified risk factor within 3 months. Data were collected as part of a
Analysis
Total RNA from 50 μL plasma was extracted with guanidinium thiocyanate14 and reverse transcribed. The first PCR was done with 0·25 μg primers Al (5′-AATTTTCCCATTGTCCTATT) and NE1 (5′-TATGTCATTGACAGTCCAGCT) for reverse-transcriptase gene sequencing, and PR49 (5′-GATGACAGCATGTCAGGGAGTA) and PR49 (5′-GATGACAGCATGTCAGGGAGTA) and PR96 (5′-CTTCCCAGAAGTCTTGAGTTCT)for protease gene sequencing. PCR was done in a reaction mixture containing 50 mmol/L potassium chloride, 10 mmol/L Tris-hydrochloric acid
Study participants
82 consecutive individuals with primary HIV-1 infection were included from January, 1996, to July, 1998. Mean age was 34 years (range 18-64), 64 (78%). were ment,. and 18 (22%), were women. The risk factors for HIV-1 infection were sex between men in 33 (40%), heterosexual sex in 33 (40%), and injecting drug use in 16 (20%). All study participants were drug naive at the time of testing. Sequence analyses were done on plasma samples collected at the first visit, before the start of
Genotypic resistance
We obtained reverse-transcriptase gene sequences for all individuals. All sequences showed a full-length open reading frame. Mutations previously associated with RTI resistance17 were seen in eight (10%) individuals (table 1). Seven individuals (9%) had mutations associated with resistance17 to zidovudine (M41L, D67N, K70R, L210W, T215Y/F). Two individuals had the mutation associated with resistance to lamivudine (MI84V) and mutations associated with resistance to nevirapine (Y181C, G190A).
We
Phenotypic resistance
We assessed sensitivity to protease inhibitors by recombinant virus assay in 14 of 16 HIV-1-infected individuals with primary or secondary mutations associated with protease-inhibitor resistance, and compared these data with data from 18 therapy-naive HIV-1-infected individuals (table 3). Three (4%) individuals with primary infection showed a significant decrease in sensitivity to protease inhibitors (more than four-fold increase in IC90 compared with controls). One individual had two primary
Transmission of multiple-drug-resistant virus
One individual (4512) was infected with HIV-1 variants that harboured 12 mutations associated with resistance to RTIs and protease inhibitors before seroconversion. This patient was infected through unprotected sex with a regular partner (source case) who was first identified as HIV-1 positive in 1989 and had received antiretroviral therapy for 4 years (zidovudine for 35 months, didanosine for 21 months, lamivudine for 24 months, stavudine for 3 months, nevirapine for 5 months, saquinavir for
Discussion
Nine (11%) of 82 individuals were infected with HIV-1 variants resistant to one or more antiretroviral drugs at the time of HIV-1 primary infection. These variants are present at seroconversion and before antiretroviral treatment. Thus, this rate reflects the frequency of transmission of resistant variants from January, 1996, to July, 1998, in a population with a wide access to newly licensed antiretroviral drugs.
The most common mutations, detected in seven (9%) individuals, were those
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