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Primary Infection, Primary Resistance.
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written by David Katzenstein, M.D.
published on HIVresistanceWeb: April 1, 1999
Late last year, Richard Hecht and his colleagues from San Francisco published a clear case of primary drug resistance, which described an individual with acute HIV infection whose virus was resistant to multiple NRTIs and PIs (see Dr. Mayers' article: Sexual Transmission of Multidrug-Resistant HIV-1) [1]. Using both env gene phylogenetic analysis and resistance testing, Hecht et al were able to demonstrate that the virus isolated from this patient (the index patient) was closely related to the virus isolated from the source patient, who had failed multiple antiretroviral regimens. The source and index patients both had genotypic evidence of resistance to AZT (mutations at codons 67, 215 and 219), 3TC (M184V mutation) and PIs (mutations at codons 46, 82 and 90, among others). Treatment of the index patient with highly active therapy, which was started within a week of infection, did not result in complete suppression of HIV RNA levels.
Earlier presentations at the Second International Workshop on HIV Drug Resistance & Treatment Strategies in Lake Maggiore, Italy, and the XII World AIDS Conference in Geneva suggested that some newly infected individuals had primary resistance with genotypic changes suggesting resistance to NRTIs, and in some cases to PIs [2,3] (see Dr. Mayers' article: Report From the Second International Workshop on Drug Resistance and Treatment Strategies: Protease Inhibitor Drug Resistance and Dr. Boucher's article: Report From the Second International Workshop on Drug Resistance and Treatment Strategies: Resistance to Reverse Transcriptase Inhibitors.). Late breakers presented at the 6th Conference on Retroviruses and Opportunistic Infections in Chicago have provided further evidence that primary resistance may be an increasing problem [4,5].
Wegner et al described a high frequency of genotypic and phenotypic resistance (21%) to at least one class of drug among newly recognized HIV infections in the US armed forces (detected in the last 3 years) [4]. A surprising finding in this cohort was the high frequency (15%) of genotypic evidence of NNRTI resistance, with nearly 8% of viral isolates from newly infected patients demonstrating high-level phenotypic resistance to delavirdine, nevirapine and efavirenz. In a community-based study of new infections presented by Susan Little, UCSD, there was a similar level of phenotypic resistance to any drug (28%), and the percentage of subjects with reduced susceptibility to the NRTIs, NNRTIs and PIs was 3%, 17%, and 13%, respectively. Two other studies, one from a Canadian consortium [6] and the other from Spain [7], reported lower incidences of primary resistance, almost exclusively to NRTIs.
These studies provide new information about the frequency of primary resistance among recently infected individuals. In both the Wegner and Little studies, there was good agreement between phenotypic and genotypic measures of resistance. Frequent detection of primary resistance among recently infected individuals suggests that secondary prevention should become a priority in the treatment of HIV infection. Education about safer sex to prevent further transmission of resistant virus must be an important part of treatment (see Dr. Bruce Polsky's article: The World is Not Flat! Safer Sex Must be the Rule!). Regional differences in the detection of resistant virus suggest that, as with microbial resistance to antibiotics, surveillance for drug-resistant HIV should be performed on a local as well as national level. Finally, whereas treatment decisions were made prior to the assessment of primary resistance in the studies discussed above, it is likely that, as the results of the GART and VIRADAPT studies are extended, resistance testing will become a part of clinical decision making, even in the drug-naïve patient (see articles by Drs. Schapiro, Roland and Conway in this edition).
Related HIVresistanceWeb Articles:
Improving HIV Therapy with Drug Resistance Genotyping: The VIRADAPT Study.
(Jonathan Schapiro, February/March 1999)
The Impact of Genotypic Antiretroviral Resistance Testing (GART) in Patients Failing Antiretroviral Therapy.
(Michelle Roland, March/April 1999)
Therapeutic Decision Making Based on Antiretroviral Drug Resistance Testing: Are We There Yet?
(Brian Conway, March/April 1999)
Sexual Transmission of Multidrug-Resistant HIV-1.
(Douglas Mayers, September/October 1998)
Report From the Second International Workshop on Drug Resistance and Treatment Strategies (24-27 June, Lake Maggiore, Italy): Protease Inhibitor Drug Resistance.
(Douglas Mayers, September/October 1998)
Report From the Second International Workshop on Drug Resistance and Treatment Strategies (24-27 June, Lake Maggiore, Italy): Resistance to Reverse Transcriptase Inhibitors.
(Charles Boucher, September/October 1998)
The World is Not Flat! Safer Sex Must be the Rule!
(Bruce Polsky, April/May 1998)
References
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- Brief Report: Sexual Transmission of an HIV-1 Variant Resistant to Multiple Reverse-Transcriptase and Protease Inhibitors.
Hecht FM, Grant RM, Petropoulos CJ, Dillon B, Chesney MA, Tian H, Nicholas S. Hellmann NS, Bandrapalli NI, Digilio L, Branson B, Kahn JO. N Engl J Med. 1998;339:1-5.
- Reverse transcriptase and protease gene analysis at the time of primary infection.
Yerly S, Kaiser L, Race E et al. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy. Abstract 107.
- Transmission of HIV-1 resistant to multiple inhibitors.
Grant RM, Hecht FM, Petropoulos CJ, et al. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy. Abstract 108.
- High frequency of antiretroviral drug resistance in HIV-1 from recently infected therapy naïve individuals.
Wegner S, Mascola J, Barile A, Aronson N, Martin G, Stephan K, Brodine S, Tasker S, Bloor S, Vingerhoets J, Hertogs K, Larder B. 6th National Conference on HIV and Opportunistic Infections. 31 Jan-4 Feb 1999, Chicago, IL.
- The spectrum and frequency of reduced antiretroviral drug susceptibility with primary HIV infection in the United States.
Little S, Daar E, Keiser P, D'Aquila R, Connick E, Hellmann N, Petropoulos C, Koup R, Rosenberg E, Walker B, Richman D. 6th National Conference on HIV and Opportunistic Infections. 31 Jan-4 Feb 1999, Chicago, IL.
- Primary antiretroviral resistance in recently infected injection drug users and in drug naïve individuals.
Alexander C, Dong W, Mo T, O'shaugnessy M, Schechter M, Montaner J, Harrigan PR. 6th National Conference on HIV and Opportunistic Infections. 31 Jan-4 Feb 1999, Chicago, IL. Abstract 218.
- Prevalence of drug resistance mutations over time in naïve HIV+ subjects living in Spain.
Gomez-Cano M, Rubio A, Puig T, Perez-Olmeda M, Ruiz L, Leal M, Clotet B, Soriano V. Presented at the 6th National Conference on HIV and Opportunistic Infections, Chicago, Feb 1-4, 1999.
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