August 7, 2008
Suzanna Attia, M.D.: Good afternoon, ladies and gentlemen. It is a pleasure to speak here at my first International AIDS Conference. So, can unsafe sex be safe? Today, we will discuss current evidence on HIV-1 transmission rates according to viral load and under the influence of highly active antiretroviral treatment and sexually transmitted infections.
To give you some context, our research is in response to a statement published in January of this year by the Swiss National AIDS Commission. This statement declared that the risk for an HIV positive person to transmit HIV through unprotected sex is less than 1 in 100,000 if that individual has a blood viral load less than 40 copies/mL for at least six months, is fully adherent to antiretroviral therapy with regular follow-up by a physician, and does not have any other sexually transmitted infections. As you may know, this statement created a large amount of controversy nationally and internationally among physicians and community alike. If you are interested, the transcript and video of a satellite session on this statement at this year's conference are available.
Our objectives: We at the Institute of Social and Preventive Medicine of the University of Bern believe that such a statement, indeed, any public health statement with such farreaching consequences demands a thorough and statistically based evaluation of current literature. Therefore, our objectives were to conduct a systematic review of longitudinal studies on HIV transmission in serodiscordant couples and where possible to perform a meta-analysis of HIV transmission rates in those with undetectable viral load without sexually transmitted infections and with and without HAART.
Our systematic review began with the search of literature from 1996 when viral load testing became widely available. We included full-length articles, citations from those articles, and abstracts of HIV discordant couples which documented HIV transmissions and viral loads in the HIV positive partner. We conducted the review according to recommended standards with two reviewers accessing eligibility and extracting data independently.
We are currently collecting additional data from authors. For studies awaiting follow-up times, we have estimated the follow-up time from the published mean or median follow-up time. Where data were available, we used a random effect model to combine results and estimate the HIV transmission rate. This method takes into accounts statistical heterogeneity in results from different studies and study populations.
In the absence of HIV transmissions, we obtained an estimate of the upper 95-percent confidence interval using an approximate method. We defined STIs as syphilis, Chlamydia, gonorrhea, or genital herpes and classified studies as STI status unclear if study authors either did not stratify their data according to the presence or absence of STIs or did not performed diagnostic tests for these infections. Our transmission rates are measured in rate per 100 person-years and not per coital act as that assessment were not extractable.
In addition, we used a limit of detection of 400 not 40 copies/mL of blood viral load as this was the limit reported in most studies. Our systematic literature search yielded 252 publications of which 241 studies were excluded due to duplication, irrelevant topic, or study design, or refusal of additional data from study authors. We were left with 14 potential cohorts comprised of seven published or in-press papers and seven studies published as abstracts.
We are still awaiting some study information and may be forced to exclude additional cohorts in our final analysis due to incomplete information.
This slide summarizes studies which we have included so far. By region, the greatest number of discordant couples and transmissions came from Africa with only 424 from Europe. Only one study noted the inclusion of men having sex with men. All other studies reported heterosexual relationships without conclusive information about the types of sexual acts. Most importantly, nine cohorts reported used of HAART in the HIV positive partner in 428 couples. In addition, eight cohorts reported some information on sexually transmitted infections among a total of 1,056 couples. We are currently awaiting clarification on these numbers.
We were able to conduct a meta-analysis to combine available data in the groups that are presented on this slide. Our systematic review did not identify any studies which fulfilled the Swiss statement criteria, that is, having individuals on HAART with an undetectable viral load and no other sexually transmitted infections. In this group, we did not include one study of 22 couples because the HIV negative partners received pre-exposure prophylaxis. Only one other study contained HIV positive individuals on HAART with undetectable viral load. However, the STI status of these individuals remains unclear.
The transmission rate in this study was 0 per 100 person-years from 283.2 person-years of follow-up. This gives an upper confidence interval of 1.06 transmissions per 100 person-year. All other studies were in HAART naive individuals. Only one transmission occurred within these groups at a level of 362 copies/mL of blood viral load.
Can unsafe sex be safe? In summary, we have not yet identified any studies which directly quantify the transmission risk of HIV positive individuals on HAART with consistently undetectable viral load and no other STIs. However, a body of indirect evidence suggests that transmission of HIV infection at low viral load levels is very rare. We did not identify any studies or case reports in which HIV transmission occurred at a viral load below 40 copies/mL.
Some limitations of our study include a lack of data on types of sexual acts and as a comment on this, a recent modeling study from Australia available on Lancet, July 26 to August 1 edition of this year, suggest that the Swiss statement may not be generalizable to men having sex with men engaging an unprotected anal sex.
In addition, we have a lack of complete data in our studies on protected and unprotected sex within our couples. Other limitations include a minimal detection of viral load assays at 400 copies/mL, as I said before, and an inability to determine the duration of viral suppression.
It is also difficult to know about the importance of STIs to HIV transmission risks in individuals on HAART because of a lack of consistent measurement of STIs significant to HIV transmission especially genital herpes and a lack of numbers on those with STI diagnoses.
It is important to note that this review is ongoing. We hope that incoming data will allow us to increase the precision of our estimates. So, is it possible for an empirical study to estimate a transmission risk of less than 1 and 100,000?
In a very simplistic calculation, if we assume a coital frequency of eight per month, it turns out that in order achieve an upper 95-percent confidence interval of 1 in 100,000, only one transmission can occur in 550,000 coital acts.
Amassing this number of coital act with the frequency of eight coital acts per month would require 1,145 couples followed for five years. We are aware of at least one study of heterosexual HIV transmission in serodiscordant couples with HAART use in the HIV positive partner. This study approaches the levels of couples in follow-up time estimated by the calculations I just mentioned and has an expected finished time of 2016.
We hope that it would, therefore, more precisely established transmission risks per coital act for the growing number of couples reaching undetectable viral loads under HAART.
It is now the accepted standard of practice to perform systematic reviews and meta-analysis in the development of statements which are intended to guide clinical decisions or public health recommendations. In addition, authors of such statements must always clarify the source, the quality, and the direct applicability of supporting evidence to the study topic.
We recommend an increase in research on HIV transmission in serodiscordant couples with the HIV positive partner on HAART and a specific investigation of the effects of different types of sexual acts symptomatic as well as asymptomatic and intermittent sexually transmitted infections as well as reproductive infections and the influence of viral load dynamics in blood and genital secretions.
We are very grateful to the study authors who actually were able to give us additional data and to those who hopefully will provide us some after their publications are done and I would personally like to thank my co-authors Matthias Egger and especially Nicola Low who is also here in the audience. Thank you for your attention. Nicola and I will be more than happy to take your questions. [Applause]
Edwin Bernard: Oh, hello! Edwin Bernard from the UK reporting for Aidsmap.
Suzanna Attia, M.D.: How are you?
Edwin Bernard: Hi. I was at the Sunday's Satellite and I remember you actually stood up and talked about how you identified the threshold of transmission being 362 copies/mL and can you tell me where that study was from and what was the next level after 362?
Suzanna Attia, M.D.: Sure. So, yes. So, the lowest detectable transmission was in 362 copies/mL as you said. This is in a study performed by Jesus Castilla in 2005 and he did the study in Spain. And I believe the next -- I do not want to give you the wrong number but I believe the next viral load was around 1,479 but I would like to just check my data and give you an accurate number.
Dr. Kubota, M.D.: Kubota from United States. What do you think the implications of the study is for seroconcordant couples who are persistently perhaps untreated persistently with negative viral loads and potentially even with same resistance backgrounds?
Suzanna Attia, M.D.: Could you please speak louder? I actually did not hear your question.
Dr. Kubota, M.D.: What are the implications for seroconcordant couples with persistently undetectable viral loads on treatment with, say for instance, the same resistance background with their viruses? Seroconcordant couples.
Suzanna Attia, M.D.: So, your question is what is the implications for seroconcordant couples? Right now, I mean, our study is focusing only serodiscordant couples and I actually cannot tell you the implications for seroconcordant. I do not know if Nicola has anything to add to that [Laughter]. No, not really. Yes, sorry. It is an excellent question, one that should be addressed by our scientific community.
Tim Farley, M.D.: Tim Farley from WHO. I much enjoyed your analysis.
Suzanna Attia, M.D.: Thank you.
Jim Farley: And I agree. The Swiss National AIDS Commission was probably a bit naughty in not doing the metaanalysis before making their recommendations and you have shown us the sort of data that would need to be there for them to make an evidence-based recommendation. However, the recommendation is out there now and I just like you to speculate what information would you have to say that their recommendation is wrong?
Suzanna Attia, M.D.: Okay, so the question is what information do we have to say that the Swiss statement is wrong?
Tim Farley, M.D.: No, I mean you do not have information to say the Swiss statement is wrong at the moment but what sort of information --
Suzanna Attia, M.D.: Do we need?
Tim Farley, M.D.: -- would you need to say that the Swiss information is wrong and how we are ever going to get that?
Suzanna Attia, M.D.: So, to make matters simple, we would need to see transmissions under 40 copies/mL. We also need a more adequate understanding of how STIs affect transmission rate because I do not think you can make a statement saying that if the partner is STI free, you will not have any transmission with undetectable viral load on HAART because we do not fully understand how frequently asymptomatic STIs for instance could happen, what the effect is on viral load and how that could actually cause a transmission over a certain period of time and not just set the point that the low viral load was measured.
Tim Farley, M.D.: Yes, okay. I mean so you are just saying that one transmission at less than 40 copies would be enough to say that the Swiss statement was wrong. Would that be enough?
Suzanna Attia, M.D.: From a logical point, that would be enough. From a statistical point, I do not think that is an accurate assessment.
Tim Farley, M.D.: Yes. The point I am getting here is we would probably never have data that would say that that statement is wrong.
Suzanna Attia, M.D.: I am sorry?
Tim Farley, M.D.: We would probably never have data to say that that statement is wrong? Unfortunately.
Suzanna Attia, M.D.: Well, hopefully, we should have a pretty accurate estimate of transmission risk in this group after the Myron Cohen Study which is the one that is finishing in 2016 is done. So, we should be able to get closer to defining, actually, how many transmissions would occur, what the risk is in that population but -- please go ahead.
Marshall D'Souza, M.D.: Hello. I am Dr. Marshall D'souza from Fort Myers Florida, United States. Mine is rather a comment rather than a question. I follow a large number of patients and I always tell them to practice safe sex but in real life, what we preach and what goes on is quite different.
Suzanna Attia, M.D.: Yes.
Marshall D'Souza, M.D.: I have serodiscordant couples wherein the man is negative and the wife or the partner is positive and the wife is doing fine on HAART, CD4 count is high, viral load is low. In spite of telling them repeatedly to practice safe sex, several of them have told me they are not practicing safe sex and the man is doing well. Some of them have come for testing and they are negative and some of them have not come for testing. So, in real life, this thing goes on what you just now discussed --
Suzanna Attia, M.D.: Yes.
Marshall D'Souza, M.D.: -- in a big way. Thank you.
Suzanna Attia, M.D.: That is a very important point. Thank you very much.