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Subtypes and resistance
Feb 21, 2005

In an answer you gave on Mar 16, 2004, you said that "There is no evidence of variations in the response of people with non-B strains to antiretroviral therapy, nor in the development of resistance to ART or in novel patterns of resistance to ART." But there seems to be a lot of studies one can find on the internet that show the opposite, such as below.

http://www.aidsmap.com/en/news/D21DBAD0-8A03-4E53-9E2D-61B7D20277BD.asp: "Laboratory studies found that sub-type C virus resistant to all the currently available NNRTIs emerged much more easily and rapidly than NNRTI resistant sub-type B virus. In addition, the investigators found some previously undetected resistance mutations to NNRTIs in sub-type C HIV. "

And this: http://jac.oupjournals.org/cgi/content/full/51/2/229 "Several studies suggest that AIDS progression differs as a function of infecting subtype.6,57,6870 In one study, patients hosting clade A or G would appear to live symptom-free for the longest, whereas those infected by clade D live an intermediate span and those hosting clade C experience rapid disease progression.70 In a recent large cohort study, subtype D was associated with lower CD4 cell count and faster disease progression and death compared with subtype A.69 Likewise, a cross-sectional study found clade C patients to suffer the highest rates of viraemia coupled with lowest CD4 counts, with progression to AIDS before their A- or D-infected counterparts.68 " And: "These findings suggest that clade C viruses can more rapidly select for resistance to NNRTIs. Recently, it was reported that non-subtype B HIV-1 strains were likely to be less susceptible to HAART.101 In addition, non-B sequences were statistically associated with rapid progression to resistance after antiretroviral therapy, and had different mutational patterns to B isolates.102 Another recent study showed some evidence of HIV-1 subtype impact on the development of NNRTI resistance mutations; there was an increased prevalence of specific mutations and polymorphisms among non-clade B viruses that may have predisposed their hosts to NNRTI treatment failure.102" And: "non-B infections are both less susceptible to HAART and statistically associated with a more rapid post-HAART progression of mutational patterns than B isolates.101,102"

I feel like I have become a researcher, probably a mistake. Thanks for your time.

Response from Dr. Sherer

Thank you for your thoughtful email. You are indeed becoming a researcher. This is a good example of both the value and the danger of the extraordinary power and access to information that the internet provides. You have challenged me on a highly important question: 'Do non-B HIV subtypes have different responses to standard ART, and different resistance patterns?' And you have indeed found sources that suggest that there is some evidence of differences between B and non-B sub-types.

I was gratified to see that Mark Wainburg's name was on the last of your references, as he is a regular source of information on this issue for me. In a plenary session at the Glasgow Conference last November, 2004, he summarized our current data in much that same way that I did in my answer in March, 2004. And yet there is the data that you cited: How can this be?

I was careful to say that differences had not emerged in the response to ART to date; with the expansion of ART in the developing world where majority populations have non-B strains,we have an increasing clincal experience. In general, it appears that excellent adherence can be achieved in these populations, and outcomes comparable to outcomes in the West and North can be achieved.

I also generalized that there do not seem to be significant major resistance patterns in non-B vs. B strains. There is a growing literature on the resistance consequences of ART failure in these populations. For example, Maggiolo presented resistance analyses of 637 patients at first regimen failure, of whom 52 had non-B strains at the Glasgow Conference (Maggiolo F, et al. HIV 7, Glasgow 2004, #P104) He did find differences, though minor and of uncertain clinical relevance, in the thymidine analogue mutations at the 215 and 41 locus (TAMS), and in some secondary protease mutations.

We should also be aware of the difficulty in answering this question simply. There is evidence in the developing world that the natural history of HIV differs, probably due in part to the poorer nutrition and the greater prevalence of other infectious diseases such as intestinal parasites. In one such study, the average time from infection to AIDS was 5 years, one half the average time in the US. While we might be tempted to attribute an observed difference in response to ART, or in the generation of mutation rates, to an intrinsic difference between B and non-B types, it may also be due in part to the host response or other environmental factors.

So, as far as it goes, I will defend my statements: So far, so good, there have been some differences identified, but they seem to be minor. I noted with interest that the papers you cited, one in particular, described a difference in sub-type C responses to NNRTIs, and NNRTI mutations, that would be of major consequences. However, it was older and small, and noted that 'larger studies would be needed to confirm.' As far as I know, larger studies have not supported this concern.

So the real answer, as is so often the case in science, is that we don't have the data yet. We don't know. That is a quite different statement than 'No difference exists.' This is a critical area for further research as we move closer to the WHO goals of treatment 3 million people worldwide by the end of this year.

Thank you again for the thoughtful email.


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