Numerous studies have shown the advantages of a number of bitherapy regimens for treatment of HIV disease as opposed to not having any access whatever to antiretroviral therapy [reviewed in 1,2]. However, it is also clear that the long-term use of bitherapy is likely to lead to the development of HIV resistance to the drugs involved in the double combinations [3,4]. In brief, this is because all bitherapy regimens have thus far been unable to effectively quench viral replication over protracted periods of time. The result is that selection of mutated HIV variants will inevitably occur and that additional mutagenesis will lead to the development of multiple drug resistance.

This problem has the potential to translate into another example of how the gaps between rich and poor countries, with respect to the benefits of HIV research and drug development, are likely to widen instead of narrow over the next several years. This is because triple-drug combinations of antiretroviral drugs (ARV's) now represent standard of care in almost all developed countries, and are able to effectively suppress viral replication far more effectively than any bitherapy regimens. Hence, viral populations in the case of people receiving triple-drug therapy, compared with people receiving double regimens, are far less likely to be capable of either replication or mutagenesis-with the consequence that drug resistance will be less likely to emerge.

In support of this concern about the likelihood of the emergence of drug resistance in developing countries, a number of presentations at the recently held 3rd International Workshop on HIV Drug Resistance and Treatment Strategies (San Diego, California, 23-26 June, 1999) dealt with the presence of resistance-conferring mutations in individuals undergoing primary infection and in other treatment-naive HIV-infected patients in western countries [5-8]. While heated discussion arose as to the clinical significance of these observations with respect to treatment options and whether the presence of such mutations, without phenotypic correlates, indeed denoted resistance, none of the presenters dealt with another major issue-the fact that this problem is likely to be far more severe in poorer countries in which the vast majority of treated patients are only able to afford a double-drug regimen. While physicians in developing countries are well aware of the unacceptability of administering monotherapy, they also know that a number of bitherapy regimens have been shown to prolong life. Moreover, problems of adherence to ARV regimes are at least as great in developing as in developed countries. Will this mean that transmission of drug-resistant forms will be more likely to occur in resource-poor countries, as more and more patients are treated with regimens that most observers in the West would consider sub-optimal?

Evidence in support of this notion emerged at the Workshop in the form of presentations that indicated that transmission of the T215Y mutation, associated with resistance to AZT, may now vary between 1 and 8% in cases of primary infection [7,8]. Yet earlier reports on this same subject had indicated higher transmission rates, on the order of 7-15% [7-11]. One of the reasons for this drop may be that the earlier studies were carried out in Western countries at a time that a much higher proportion of patients than at present received bitherapy. Hence, the likelihood of transmission of resistant strains in developed countries may continue to diminish as even more efficient treatment strategies emerge. At precisely the same time, the problem will probably continue to grow in many of the countries of Africa, Asia, and Eastern Europe.

HIV-infected persons in developing countries have a right to be treated with the best therapies that they and/or their governments can afford. However, the potential for increased levels of drug resistance in such settings, and the transmission of resistant variants, should not be ignored. In the short term, the following considerations and questions should be highlighted:

1. Are those viruses that are currently responsible for high rates of HIV spread in developing countries (i.e., clades C and E) potentially more replication-competent and virulent than the clade B viruses that have been well characterized in regard to drug resistance in western countries. What will be the consequence of the spread of clade C and E viruses in Western countries? We immediately need to do research to determine whether the resistance-conferring mutations in both the RT and protease genes of clade B viruses, that have been reasonably well characterized, play identical roles in viruses of other clades. Answers to these questions will impact the suitability of applying currently available sequencing and hybridization tests for detection of specific resistance-associated mutations to viruses of other clades.
2. Recent results have pointed to the use of nevirapine, administered to birthing mothers as a single dose at the beginning of labor and as a single dose administered to infants shortly after birth, as a means of cutting perinatal transmission of HIV by 50% in comparison to use of AZT. We know that only a single mutation in RT is required to confer high-level resistance to nevirapine. However, the fact that so few people in developing countries currently receive nevirapine means that the problem of resistance to NNRTIs in such settings is unlikely to become important in terms of numbers for at least several years. Nonetheless, we must be vigilant or we may ultimately have to deal with a situation in which our ability to prevent transmission of HIV from infected mothers to infants would potentially be compromised by the widespread occurrence of NNRTI-resistant HIV. Conceivably, as well, the most important future source of drug-resistant viruses, in the context of primary infection in the West, may be developing countries in which bitherapy is commonplace rather than from our own patients who mostly have access to triple or quadruple ARV regimens.
   
   
   

   References

   Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel.   Carpenter CC, Fischl MA, Hammer SM, et al. JAMA.1998; 280:78-86. Public health implications of antiretroviral therapy and HIV drug resistance.  Wainberg MA, Friedland G. JAMA. 1998; 279: 1977-83. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy.  Gulick RM, Mellors JW, Havlir D, et al. N Engl J Med. 1997; 337: 734-739. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV- infected patients: the INCAS Trial.  Montaner JSG, Reiss P, Cooper D, et al. JAMA. 1998; 279: 930-937. Prevalence of HIV-1 drug resistance mutations in 80 newly infected individuals. Abstracts of the 3rd International Workshop on HIV Drug Resistance and Treatment Strategies.  Boden D, Hurley A, Zhang L, et al. Antiviral Therapy. 1999; 4 (supplement 1): Abstract no. 85. The spectrum and frequency of reduced antiretroviral drug susceptibility with primary HIV infection in the United States. Abstracts of the 3rd International Workshop on HIV Drug Resistance and Treatment Strategies.   Little S, Daar E, Keiser P, et al. Antiviral Therapy. 1999; 4 (supplement 1): Abstract no. 86. Trends in prevalence of primary HIV-1 drug resistance among recently infected persons in San Francisco. Abstracts of the 3rd International Workshop on HIV Drug Resistance and Treatment Strategies.  Grant RM, Hecht FM, Petropoulos CJ, et al. Antiviral Therapy. 1999; 4 (supplement 1): Abstract no. 98. Prevalence of mutations associated with antiretrovial drug resistance among HIV-1 seroconverters in the USA, 1993-1998. Abstracts of the 3rd International Workshop on HIV Drug Resistance and Treatment Strategies.   Weinstock H, Respess R, Heneine W, et al. Antiviral Therapy. 1999; 4(supplement 1): Abstract no. 99. Pr&eactute;valence de la transmission de virus r&eactute;sistant à la zidovudine en Suisse  Yerly S, Rakik A, Kinloch-de-Loes S, et al. Scheweiz Med Wochenschr 1996; 126: 1845-1848. Increase in the frequency of mutation at condon 215 associated with zidovudine resistance in HIV-1 infected antiviral-naïve patients from 1989 to 1996.  Rubio A, Leal M, Pineda JA, et al. AIDS. 1997; 11:1184-1186. Mutations associated with zidovudine resistance in HIV-1 among recent seroconvertors.  Quigg M, Rebus S, France AJ, et al. AIDS. 1997; 11: 835-836.

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