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Primary Infection with Drug Resistant HIV-1: Update
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written by Douglas Mayers, M.D.
published on HIVresistanceWeb: September 2, 1999
The HIV primary infection presentations at the Resistance Meeting showed continued progress in developing systems to evaluate the incidence and prevalence of drug resistant HIV-1 but also revealed several significant systemic flaws which need to be addressed in the coming year.
Dr. Descamps presented data from the French National Study of virus from antiretroviral-naïve patients [1] which showed data from 253 male and 74 female patients followed at 23 AIDS care centers in France. 24% of the patients were seropositive for less than 1 year and 76% were seropositive for more than one year (median 5.3 years). Drug resistance was determined by sequencing plasma virus. Of note, in patients with < 1 year since seroconversion, major resistance mutations were detected for NRTI in 3.3 % of patients, NNRTI in 0.7% of patients versus 0.2% NRTI and 0.4% NNRTI for patients seen > 1 year after HIV seroconversion. Resistance to multiple drugs was detected in three recently infected patients. The reasons for the low levels of resistance detected in patients infected for more than one year are uncertain but could include reversion of drug resistant virus in the absence of treatment or low levels of transmission of drug resistant virus until the recent past. On the basis of this data, the recommendations in France are to perform resistance genotyping prior to treatment on patients who are recently infected (< 1 year) but not on patients who were infected for more than one year.
Three groups presented data from large seroconverter cohorts that have been followed over the last several years.
This data is summarized in the Table below:
Table 1. Prevalence of HIV-1 Drug Resistance in Recently Infected Persons (High level drug resistance)
Presenter (Abst) |
# Persons |
Study years |
Genotypic resistance (%) |
Phenotypic resistance (%) |
| |
|
|
NRTI |
NNRTI |
PI |
NRTI |
NNRTI |
PI |
Wegner (119) |
114
|
1996-1999 |
1.0 |
1.0 |
1.0 |
1.0 |
7.7 |
1.0 |
Boden (120) |
80 |
1995-1999 |
12.5 |
7.5 |
2.5 |
|
|
|
Little (121) |
133 |
1990-1998 |
|
|
|
2.0 |
1.0 |
2.0 |
Overall rates of drug resistance for the studies (as defined by each presenter) were 21% of patients [2], 22.5% of patients [3], and 29% of patients [4]. The differences in overall rates of resistance and the rates shown in Table 1 result from larger numbers of patients with possible genotypic drug resistance or intermediate levels of phenotypic drug resistance.
There was also the suggestion that drug resistance transmission may be heterogeneous in different locations and patient populations with recent increased drug resistance seen in New York [3] and decreasing rates seen in San Francisco [5].
Several significant shortcomings in the area of drug resistance monitoring were highlighted by these presentations:
- Genotypic resistance testing. There is no consensus yet on how to interpret resistance mutations. This led to some groups calling an amino acid change a mutation that other groups had termed a polymorphism. Until some consensus can be achieved there will be difficulty comparing data between the different groups unless individual patient data is shown.
- Phenotypic resistance testing. There is a real concern that the reference range for NNRTI resistance may have been set too low by the phenotyping companies, leading to inflated rates of low level NNRTI resistance in these surveys. Previously, the susceptible or normal drug sensitivity range for an individual drug was determined by testing a number of clinical HIV isolates from drug-naïve individuals. Currently for the recombinant virus assays, the reference range is defined by the susceptibility of a reference wild-type virus used by the manufacturer. There is a wide variability in drug susceptibilities for wild type virus and it appears that the thresholds for resistance defined by the companies (2.5 to 5 times WT IC50 of their reference strain) may be too low. The companies need to evaluate a panel of wild type viruses from clinical samples obtained prior to 1987 to determine the "susceptible" range for each drug and then they should reanalyze their data.
- Real time data. Public policy decisions regarding the potential utility or public health impact of primary infection with drug resistant HIV-1 require the availability of current data, obtained within the past 6 to 12 months. The majority of data presented at the meeting was from HIV seroconvesions that occurred more than a year ago, and none of the groups presenting had enough current data to show accurately what is happening at the present time, after the widespread use of HAART therapy. A voluntary meta-analysis of real time data from recent seroconverters is necessary, maintained either by an independent party such as the Centers for Disease Control or voluntarily conducted by investigators prior to the next meeting. It is no longer adequate to present data from the past three years to determine the impact of HIV drug resistance in 1999. A real time monitoring capability must be developed to make good public policy decisions in this area. Hopefully this void will be filled prior to the next Resistance Meeting.
References
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- Prevalence of resistance mutations in antiretroviral-naïve patients: French National Study
; D Descamps, D Costagliola, G Glaude; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 123
- High frequency of antiretroviral drug resistance in HIV-1 from recently infected therapy-naïve individuals
; S Wegner, S Brodine, J Mascola; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 119
- Prevalence of HIV-1 drug resistance mutations in 80 newly infected individuals
; D Boden, A Hurley, L Zhang; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 120
- The spectrum and frequency of reduced antiretroviral drug susceptibility with primary HIV infection in the United States
; S Little, E Daar, P Keiser; Antiviral Therapy 1999; (Supplement 1): Abstract 121
- Trends in prevalence of primary HIV-1 drug resistance among recently infected persons in San Francisco
; RM Grant, FM Hecht, CJ Petropoulos; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 142
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