Keynote Session on Drug-Resistant HIV, TB, and Malaria
Keynote Session on Drug-Resistant HIV, TB, and Malaria
The Opening Session of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy featured 3 presentations concerning antimicrobial resistance as it relates to the 3 top microbial causes of death: HIV, Mycobacteriumtuberculosis, and malaria. Daniel Kuritzkes, MD, from Brigham and Woman's Hospital, Cambridge, Massachusetts, reviewed the "big picture" regarding resistance of HIV in the 16th year of antiretroviral therapy and the 8th year of highly active antiretroviral therapy (HAART).
Data on the prevalence of resistance was reviewed from the HIV Service and Cost Utilization Survey (HSCUS) in 1998, which provided a national sampling for patients receiving antiretroviral therapy. The frequency of resistance to any drug (among treated patients with > 1000 HIV-1 RNA copies/mL) was 78%; for nucleoside reverse transcriptase inhibitors (NRTIs), 70%; for nonnucleoside reverse transcriptase inhibitors (NNRTIs), 31%; for protease inhibitors (PIs), 42%; for > 2 classes, 51%. Extrapolated to the general population, including those without detectable resistance due to viral suppression, the conclusion is that about half of treated patients have resistance mutations. With regard to newly infected patients, data from Little and coworkers have shown sequential increases in resistance from 1995 to 2000, which indicates an increasing pool of resistant strains in more recently transmitted HIV cases.
The mechanism of resistance is complex: Viral populations are composed of quasispecies; replication is associated with a high mutational error rate; viral turnover is rapid; genetically distinct variants evolve from oligoclonal inocula; antivirals apply selective pressure; and latently infected cells provide a reservoir for resistant strains. Contributing factors include poor adherence, host factors including human lymphocyte antigen (HLA) haplotype, pharmacodynamics, drug potency, and transmitted drug resistance.
Some of the lessons learned in resistance studies are that pathways may vary by HIV subtype. For example, nelfinavir selects for D30N in subtype B strains but for L90M in non-B subtype strains -- a possibly important issue when antivirals are used in resource-limited countries. ACTG 398 illustrated the problem of the viral reservoir in resistance to efavirenz. Dr. Kuritzkes warned of the potential consequences of single-dose nevirapine to prevent mother-to-child HIV transmission in resource-limited areas based on this observation.
With regard to adherence, the point was again emphasized that poor compliance is associated with minimal pressure and low frequency of resistance; good adherence may paradoxically lead to the high rate of resistance.
The concepts of fitness (relative replication success in a given environment), replication capacity (number of progeny produced), and virulence (ability to kill CD4+ cells) are important in understanding several clinical observations. An example is the increased viral load and rapid CD4 decline after structured treatment interruption (STI) used in the setting of virologic failure. This is best explained by some combination of residual antiviral activity and reduced replicative capacity. Recent studies by Deeks and colleagues suggest that NRTIs may be more important than PIs in maintaining stability after failed regimens.
Final comments concerned the use of antiretrovirals in resource-limited areas. Points emphasized were: (1) there is no evidence that adherence will represent a greater problem in these settings compared with other areas; (2) the greatest risk is introduction of these drugs without regulation; (3) there is a need for regimens with potency and simplicity; (4) the expedient approach of partially suppressive regimens to reduce cost is a bad idea; and (5) non-subtype B strains are different, and differing efficacy rates may be observed compared with subtype B strains.
Tuberculosis
Lee Reichman, MD, MPH, from the National Tuberculosis Center, Newark, New Jersey, reviewed the issue of multidrug-resistant tuberculosis (MDRTB). For perspective, he noted that TB accounts for 2 million deaths per year, and 98% of TB morbidity and mortality occurs in developing countries. MDRTB is defined by resistance to isoniazid (INH) and rifampin. A recent global review showed that the prevalence of MDRTB is 3.2% among new TB cases. The problems that accompany MDRTB are: (1) treatment takes longer -- up to 24 months; (2) treatment is 100 times more expensive (World Health Organization [WHO] drug price for standard regimen is $10 to $50, and for MDRTB the average is $19,000); (3) there are far more side effects; and (4) it requires complex diagnostics.
The mechanism of resistance is man-made and reflects the problem of incomplete therapy. The frequency of INH resistance mutations in tuberculosis bacilli is 1/10; for rifampin, 1/10; ethambutol, 1/10; and streptomycin 1/10. With combined INH and rifampin it is 1/10; the number of bacilli in a TB cavity is 10 so these drugs, properly given, won't cause resistance.
The best method to deal with MDRTB is the WHO DOTS (Directly Observed Treatment, Short-course) program, which requires 5 drugs, government commitment, smear for diagnosis, standard short-course therapy, and adequate drug supply and record keeping. With this program, the cure rate is 95%. DOTS-PLUS adds case management for MDRTB with second-line agents: kanamycin, amikacin, capreomycin, cycloserine, fluoroquinolones, p-aminosalicylic acid (PAS), and ethionamide. These drugs are included in the WHO essential drug list. They are associated with substantial complexity, including increased toxicity, longer duration, higher cost, and reduced supply. The temptation is to deal with drug-sensitive TB because it is far more economical. The Green Light Committee was created to attend to this issue; this multinational group provides preferentially priced drugs (at 1% to 5% of standard prices), a decision process, monitoring, and technical assistance.
Malaria
Nicholas White, SCD, from Mahidol University, Bangkok, Thailand, reviewed malaria resistance and the global problem representing selective pressure with de novo selection caused by subtherapeutic treatments. This occurs with the following frequencies: pyrimethamine, 1/10; atovaquone, 1/10; mefloquine, 1/10; and chloroquine 1/10. The only drug that retains universal activity is artemisinin.
As with TB, the probability of malarial resistance is a chance mutational change: For 2 drugs with a resistance rate of 1/10 bacilli, the probability of simultaneous resistance is 1/10. There are only 10-10 malaria parasites in the world. Thus, the solution is combination therapy, such as artesunate and mefloquine. This treatment needs to be inexpensive ($1), have a short course (3 days), be provided in fixed combinations, and have good tolerance to promote adherence. These goals have been achieved.
Summary
There were several unifying themes in these 3 presentations: (1) the greatest burden of disease exists in resource-limited countries that account for 95% to 98% cases of all 3 diseases; (2) resistance is man-made and based on selective pressure with regimens that have inadequate potency; and (3) all 3 conditions require combination therapy. Furthermore, these diseases are influenced by critical variables, such as microbial burden, drug potency, adherence, and cost of care.
References
The Opening Session of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy featured 3 presentations concerning antimicrobial resistance as it relates to the 3 top microbial causes of death: HIV, Mycobacteriumtuberculosis, and malaria. Daniel Kuritzkes, MD, from Brigham and Woman's Hospital, Cambridge, Massachusetts, reviewed the "big picture" regarding resistance of HIV in the 16th year of antiretroviral therapy and the 8th year of highly active antiretroviral therapy (HAART).
Data on the prevalence of resistance was reviewed from the HIV Service and Cost Utilization Survey (HSCUS) in 1998, which provided a national sampling for patients receiving antiretroviral therapy. The frequency of resistance to any drug (among treated patients with > 1000 HIV-1 RNA copies/mL) was 78%; for nucleoside reverse transcriptase inhibitors (NRTIs), 70%; for nonnucleoside reverse transcriptase inhibitors (NNRTIs), 31%; for protease inhibitors (PIs), 42%; for > 2 classes, 51%. Extrapolated to the general population, including those without detectable resistance due to viral suppression, the conclusion is that about half of treated patients have resistance mutations. With regard to newly infected patients, data from Little and coworkers have shown sequential increases in resistance from 1995 to 2000, which indicates an increasing pool of resistant strains in more recently transmitted HIV cases.
The mechanism of resistance is complex: Viral populations are composed of quasispecies; replication is associated with a high mutational error rate; viral turnover is rapid; genetically distinct variants evolve from oligoclonal inocula; antivirals apply selective pressure; and latently infected cells provide a reservoir for resistant strains. Contributing factors include poor adherence, host factors including human lymphocyte antigen (HLA) haplotype, pharmacodynamics, drug potency, and transmitted drug resistance.
Some of the lessons learned in resistance studies are that pathways may vary by HIV subtype. For example, nelfinavir selects for D30N in subtype B strains but for L90M in non-B subtype strains -- a possibly important issue when antivirals are used in resource-limited countries. ACTG 398 illustrated the problem of the viral reservoir in resistance to efavirenz. Dr. Kuritzkes warned of the potential consequences of single-dose nevirapine to prevent mother-to-child HIV transmission in resource-limited areas based on this observation.
With regard to adherence, the point was again emphasized that poor compliance is associated with minimal pressure and low frequency of resistance; good adherence may paradoxically lead to the high rate of resistance.
The concepts of fitness (relative replication success in a given environment), replication capacity (number of progeny produced), and virulence (ability to kill CD4+ cells) are important in understanding several clinical observations. An example is the increased viral load and rapid CD4 decline after structured treatment interruption (STI) used in the setting of virologic failure. This is best explained by some combination of residual antiviral activity and reduced replicative capacity. Recent studies by Deeks and colleagues suggest that NRTIs may be more important than PIs in maintaining stability after failed regimens.
Final comments concerned the use of antiretrovirals in resource-limited areas. Points emphasized were: (1) there is no evidence that adherence will represent a greater problem in these settings compared with other areas; (2) the greatest risk is introduction of these drugs without regulation; (3) there is a need for regimens with potency and simplicity; (4) the expedient approach of partially suppressive regimens to reduce cost is a bad idea; and (5) non-subtype B strains are different, and differing efficacy rates may be observed compared with subtype B strains.
Tuberculosis
Lee Reichman, MD, MPH, from the National Tuberculosis Center, Newark, New Jersey, reviewed the issue of multidrug-resistant tuberculosis (MDRTB). For perspective, he noted that TB accounts for 2 million deaths per year, and 98% of TB morbidity and mortality occurs in developing countries. MDRTB is defined by resistance to isoniazid (INH) and rifampin. A recent global review showed that the prevalence of MDRTB is 3.2% among new TB cases. The problems that accompany MDRTB are: (1) treatment takes longer -- up to 24 months; (2) treatment is 100 times more expensive (World Health Organization [WHO] drug price for standard regimen is $10 to $50, and for MDRTB the average is $19,000); (3) there are far more side effects; and (4) it requires complex diagnostics.
The mechanism of resistance is man-made and reflects the problem of incomplete therapy. The frequency of INH resistance mutations in tuberculosis bacilli is 1/10; for rifampin, 1/10; ethambutol, 1/10; and streptomycin 1/10. With combined INH and rifampin it is 1/10; the number of bacilli in a TB cavity is 10 so these drugs, properly given, won't cause resistance.
The best method to deal with MDRTB is the WHO DOTS (Directly Observed Treatment, Short-course) program, which requires 5 drugs, government commitment, smear for diagnosis, standard short-course therapy, and adequate drug supply and record keeping. With this program, the cure rate is 95%. DOTS-PLUS adds case management for MDRTB with second-line agents: kanamycin, amikacin, capreomycin, cycloserine, fluoroquinolones, p-aminosalicylic acid (PAS), and ethionamide. These drugs are included in the WHO essential drug list. They are associated with substantial complexity, including increased toxicity, longer duration, higher cost, and reduced supply. The temptation is to deal with drug-sensitive TB because it is far more economical. The Green Light Committee was created to attend to this issue; this multinational group provides preferentially priced drugs (at 1% to 5% of standard prices), a decision process, monitoring, and technical assistance.
Malaria
Nicholas White, SCD, from Mahidol University, Bangkok, Thailand, reviewed malaria resistance and the global problem representing selective pressure with de novo selection caused by subtherapeutic treatments. This occurs with the following frequencies: pyrimethamine, 1/10; atovaquone, 1/10; mefloquine, 1/10; and chloroquine 1/10. The only drug that retains universal activity is artemisinin.
As with TB, the probability of malarial resistance is a chance mutational change: For 2 drugs with a resistance rate of 1/10 bacilli, the probability of simultaneous resistance is 1/10. There are only 10-10 malaria parasites in the world. Thus, the solution is combination therapy, such as artesunate and mefloquine. This treatment needs to be inexpensive ($1), have a short course (3 days), be provided in fixed combinations, and have good tolerance to promote adherence. These goals have been achieved.
Summary
There were several unifying themes in these 3 presentations: (1) the greatest burden of disease exists in resource-limited countries that account for 95% to 98% cases of all 3 diseases; (2) resistance is man-made and based on selective pressure with regimens that have inadequate potency; and (3) all 3 conditions require combination therapy. Furthermore, these diseases are influenced by critical variables, such as microbial burden, drug potency, adherence, and cost of care.
References
Kurtizkes DR. Drug resistance: lessons learned from HIV. Program and abstracts of the 43rd Annual ICAAC; September 14-17, 2003; Chicago, Illinois. Abstract 586.
Little SJ, Holte S, Routy JP, et al. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med. 2002;347:385-394.
Deeks SG, Martin JN, Hoh R, Wrin T, Petropoulos C, Grant RM. Continued reverse transcriptase inhibitor therapy is sufficient to maintain short-term partial suppression of multi-drug resistant viremia. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 640.
Reichman L. Tuberculosis. Program and abstracts of the 43rd Annual ICAAC; September 14-17, 2003; Chicago, Illinois. Abstract 587.
White NJ. Malaria. Program and abstracts of the 43rd Annual ICAAC; September 14-17, 2003; Chicago, Illinois. Abstract 588.