HIV Drug Resistance Update
HIV Drug Resistance Update
Two oral sessions (and scores of excellent posters) on Monday, February 9, were dedicated to the topic of HIV drug resistance. Following are some highlights of new findings concerning this key topic.
In an oral presentation, Michael Kozal of Yale University School of Medicine, New Haven, Connecticut, demonstrated that a very small proportion (approximately 7%) of HIV-infected individuals who have developed drug resistance as a consequence of long-term treatment and/or treatment failure are responsible for a relatively high proportion of transmission of drug-resistant viruses or viruses containing resistance-related mutations in the United States. This finding is of obvious importance with respect to public health and the design of interventions, and suggests the need for better education and/or other measures to deal with the fact that some people who harbor drug-resistant viruses are engaging in unprotected sex with multiple partners. However, it should be noted that this was a relatively small, Connecticut-based study that also dealt with behavioral intervention. Thus, the results cannot be generalized until confirmatory data are obtained from other studies. Also, the types of subjects who enroll in this type of study may have different behavioral patterns from those who do not, and this may be a confounder in regard to the interpretation of the results.
Several studies focused on the use of nevirapine in protocols to prevent mother-to-child transmission of HIV(MTCT). Previous research has shown that resistance to nevirapine can occur in mothers after exposure to a single dose of the drug in this context. In a French/Thai study, the investigators concluded that the addition of a single dose of nevirapine to a zidovudine regimen for preventing MTCT had considerable benefit over a placebo-controlled arm in which only zidovudine was employed. A second, separate study, however, showed that resistance to nevirapine was probably responsible for poorer virologic outcomes in women who were exposed to nevirapine in MTCT protocols and were subsequently treated with nevirapine-containing regimens for HIV disease. In a related study, investigators reported high rates of resistance to nevirapine among both mothers and infants who had been exposed to single doses of this drug.
John Mellors of the University of Pittsburgh, Pittsburgh, Pennsylvania, shed important light on the issue of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance by demonstrating that resistance to this class of drugs may sometimes exist at levels that are too low for detection by commercially available genotyping procedures. This study took advantage of clinical samples from ACTG study 398, in which patients had been treated with a variety of antiretroviral agents, including efavirenz. The results showed that patients whose virus possessed NNRTI mutations that could only be detected by ultrasensitive procedures were less likely to have good responses to NNRTIs than those whose did not. This work also highlights the fragility of the NNRTI family of currently approved drugs in regard to the problem of drug resistance. Of note, this theme was picked up by another group of researchers who showed that preexisting minority viral populations containing polymorphisms in the viral protease gene can likewise predispose for the rapid development of resistance to protease inhibitors (PIs), following introduction of a PI-containing regimen.
Susan Little of the University of California, San Diego, reported on the persistence of transmitted drug-resistant HIV variants after acute infection. In her study, the initial mutational profiles of viral isolates was found to persist for over 3 years in 9 of 11 subjects who were initially infected with drug-resistant HIV. The loss of the NNRTI-associated K103N mutation was a relatively rare event and the loss of mutations associated with PI resistance was not observed at all.
With respect to nucleoside and nucleotide reverse transcriptase inhibitor resistance, Joseph Jemsek of the Jemsek Clinic in Huntersville, North Carolina, presented his group's findings that a once-daily regimen of tenofovir/didanosine/lamivudine failed to significantly reduce viral load in a high proportion of individuals, and that this was associated with the development of the K65R mutation. As have others before it, this study raises the possibility of adverse drug interactions among several of the drugs in the regimen that may have precluded its satisfactory effectiveness. Whether such interactions also may have facilitated the selection of K65R is not known. However, this latter explanation does not appear to be implausible.
This notion of unfavorable drug interactions -- and their potential contribution to the selection of the K65R mutation -- had been suggested previously by high rates of treatment failure observed in patients receiving a once-daily regimen of tenofovir/abacavir/lamivudine (eg, in the ESS 30009 study; see Medscape's Expert Interview from ICAAC
[http://www.medscape.com/viewarticle/462055]). A French study presented at the CROI meeting suggested that the failure of this regimen and the rapid selection of K65R might be due to the low genetic barrier to resistance presented by the drugs in the regimen. Of note, a separate study demonstrated that far better results could be obtained with a once-daily 4-drug regimen that included zidovudine (ie, Trizivir/tenofovir). These findings are consistent with previous observations that zidovudine can help protect against the selection of the K65R mutation.
References
Two oral sessions (and scores of excellent posters) on Monday, February 9, were dedicated to the topic of HIV drug resistance. Following are some highlights of new findings concerning this key topic.
In an oral presentation, Michael Kozal of Yale University School of Medicine, New Haven, Connecticut, demonstrated that a very small proportion (approximately 7%) of HIV-infected individuals who have developed drug resistance as a consequence of long-term treatment and/or treatment failure are responsible for a relatively high proportion of transmission of drug-resistant viruses or viruses containing resistance-related mutations in the United States. This finding is of obvious importance with respect to public health and the design of interventions, and suggests the need for better education and/or other measures to deal with the fact that some people who harbor drug-resistant viruses are engaging in unprotected sex with multiple partners. However, it should be noted that this was a relatively small, Connecticut-based study that also dealt with behavioral intervention. Thus, the results cannot be generalized until confirmatory data are obtained from other studies. Also, the types of subjects who enroll in this type of study may have different behavioral patterns from those who do not, and this may be a confounder in regard to the interpretation of the results.
Several studies focused on the use of nevirapine in protocols to prevent mother-to-child transmission of HIV(MTCT). Previous research has shown that resistance to nevirapine can occur in mothers after exposure to a single dose of the drug in this context. In a French/Thai study, the investigators concluded that the addition of a single dose of nevirapine to a zidovudine regimen for preventing MTCT had considerable benefit over a placebo-controlled arm in which only zidovudine was employed. A second, separate study, however, showed that resistance to nevirapine was probably responsible for poorer virologic outcomes in women who were exposed to nevirapine in MTCT protocols and were subsequently treated with nevirapine-containing regimens for HIV disease. In a related study, investigators reported high rates of resistance to nevirapine among both mothers and infants who had been exposed to single doses of this drug.
John Mellors of the University of Pittsburgh, Pittsburgh, Pennsylvania, shed important light on the issue of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance by demonstrating that resistance to this class of drugs may sometimes exist at levels that are too low for detection by commercially available genotyping procedures. This study took advantage of clinical samples from ACTG study 398, in which patients had been treated with a variety of antiretroviral agents, including efavirenz. The results showed that patients whose virus possessed NNRTI mutations that could only be detected by ultrasensitive procedures were less likely to have good responses to NNRTIs than those whose did not. This work also highlights the fragility of the NNRTI family of currently approved drugs in regard to the problem of drug resistance. Of note, this theme was picked up by another group of researchers who showed that preexisting minority viral populations containing polymorphisms in the viral protease gene can likewise predispose for the rapid development of resistance to protease inhibitors (PIs), following introduction of a PI-containing regimen.
Susan Little of the University of California, San Diego, reported on the persistence of transmitted drug-resistant HIV variants after acute infection. In her study, the initial mutational profiles of viral isolates was found to persist for over 3 years in 9 of 11 subjects who were initially infected with drug-resistant HIV. The loss of the NNRTI-associated K103N mutation was a relatively rare event and the loss of mutations associated with PI resistance was not observed at all.
With respect to nucleoside and nucleotide reverse transcriptase inhibitor resistance, Joseph Jemsek of the Jemsek Clinic in Huntersville, North Carolina, presented his group's findings that a once-daily regimen of tenofovir/didanosine/lamivudine failed to significantly reduce viral load in a high proportion of individuals, and that this was associated with the development of the K65R mutation. As have others before it, this study raises the possibility of adverse drug interactions among several of the drugs in the regimen that may have precluded its satisfactory effectiveness. Whether such interactions also may have facilitated the selection of K65R is not known. However, this latter explanation does not appear to be implausible.
This notion of unfavorable drug interactions -- and their potential contribution to the selection of the K65R mutation -- had been suggested previously by high rates of treatment failure observed in patients receiving a once-daily regimen of tenofovir/abacavir/lamivudine (eg, in the ESS 30009 study; see Medscape's Expert Interview from ICAAC
[http://www.medscape.com/viewarticle/462055]). A French study presented at the CROI meeting suggested that the failure of this regimen and the rapid selection of K65R might be due to the low genetic barrier to resistance presented by the drugs in the regimen. Of note, a separate study demonstrated that far better results could be obtained with a once-daily 4-drug regimen that included zidovudine (ie, Trizivir/tenofovir). These findings are consistent with previous observations that zidovudine can help protect against the selection of the K65R mutation.
References
Kozal M, Amico R, Chiarella J, et al. Continuing high-risk sexual behavior and increasing antiretroviral resistance among HIV patients in care helps explain the rising prevalence of resistance among new HIV infections. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 35LB.
Lallemant M, Jourdain G, Le Coeur S, et al. A randomized, double-blind trial assessing the efficacy of single-dose perinatal nevirapine added to a standard zidovudine regimen for the prevention of mother-to-child transmission of HIV-1 in Thailand. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 40LB.
Jourdain G, Ngo-Giang-Huong N, Tungyai P, et al. Exposure to intrapartum single-dose nevirapine and subsequent maternal 6-month response to NNRTI-based regimens. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 41LB.
Martinson N, Morris L, Gray G, et al. HIV resistance and transmission following single-dose nevirapine in a PMTCT cohort. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 38.
Mellors J, Palmer S, Nissley D, et al. Low-frequency NNRTI-resistant variants contribute to failure of efavirenz-containing regimens. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 39.
Charpentier C, Morand-Joubert L, Chene G, Girard P-M, Clavel F, Hance AJ. Detection of pre-existing minority viral populations contributing to the evolution of resistance to protease inhibitors. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 57.
Little SJ, Koelsch KK, Ignacio CC, et al. Persistence of transmitted drug-resistant virus among subjects with primary HIV infection deferring antiretroviral therapy. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 36LB.
Jemsek J, Hutcherson P, Harper E. Poor virologic and early emergence of resistance in treatment naive, HIV-infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 51.
Landman R, Peytavin G, Descamps D, et al. Low genetic barrier to resistance is a possible cause of early virologic failures in once-daily regimen of abacavir, lamivudine, and tenofovir: the tonus study. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 52.
Elion R, Cohen C, DeJesus E, et al. COL40263: resistance and efficacy of once-daily Trizivir and tenofovir DF in antiretroviral naive subjects. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 53.
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