CROI 2009: report back from Montreal.
The Conference on Retroviruses and Opportunistic Infections
(affectionately known as 'CROI' by regulars) is held annually
in North America. The conference is acknowledged as a showpiece
scientific HIV event, keenly observed by commentators for new moves
forward in a rapidly evolving field. This year it was held in icy
Montreal, with over 4 000 delegates and tons of useful science.
Most of the presentations are freely webcast on an excellent website, unusual in the broader money-making world of medical conferencing (see http://www.retroconference.org/2009/, go to the webcasts/podcasts, then to day of the week--there is also a host of excellent scientific commentary at http://www.i-base.info/index.html and http:// www.aidsmap.com/en/default.asp, all freely available).
The huge amount of high-quality research from southern Africa was remarkable, even by standards set at CROI just 3 years ago. This report focuses on key studies that may have impact in our region (and the authors may have missed several important ones, as it was impossible to attend everything). The day of the week is mentioned below, so that the reader can quickly find the webcast.
HIV (Viruses) (Health aspects)
|Publication:||Name: Southern African Journal of HIV Medicine Publisher: South African Medical Association Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 South African Medical Association ISSN: 1608-9693|
|Issue:||Date: Summer, 2009 Source Volume: 10 Source Issue: 1|
MOMS AND KIDS STEAL THE SHOW
Prevention of mother-to-child transmission (PMTCT), breastfeeding, maternal health and antiretroviral coverage featured prominently at the conference, and are of obvious concern to clinicians and programme managers in our region. Our own James McIntyre and Glenda Grey from the Perinatal HIV Research Unit (PHRU) kicked things off with a Memorial Lecture (Sunday), a very entertaining, unique and at times savage discussion of South Africa's HIV programme and history, with special mention of the PMTCT programme.
Jeff Stringer did a HIV breastfeeding transmission overview on Wednesday morning. Stringer, drawing on his experience in working in Zambia, was reflective and very interesting, teasing out the complexity of what seems on the surface a very easy topic. Some good news was that a study from Botswana showed that women who breastfeed had the same mortality as those who didn't (other older studies have shown worrying data that breastfeeding mothers may have higher mortality); another from Malawi showed that maternal antiretroviral therapy (ART) dramatically reduced breastmilk HIV transmission. Finally, hormonal contraception was shown not to impact on progression to AIDS, another area of controversy and concern from previous studies (Wednesday).
One of the scariest pieces of research at the conference was on acute seroconversion in pregnancy and breastfeeding, from Botswana. Botswana boasts a very good PMTCT programme and has demonstrated a dramatic decrease in transmission over the past few years. Acute seroconversion is a highly infectious stage of the disease; if a pregnant mom seroconverts, or if a woman is infected during breastfeeding, infection of the fetus or infant is highly likely. This study showed that acquiring HIV during pregnancy/breastfeeding now accounts for almost half of all PMTCT transmission in Botswana. It is unclear what can be done about it (besides pre-exposure prophylaxis for all pregnant HIV-negative women, or simply decreasing adult prevalence), as the normal PMTCT interventions are unlikely to work, and repeated HIV testing to catch infection early is probably not good enough. This study has huge implications for high-prevalence areas, as it suggests that eradicating paediatric HIV is impossible, unless HIV prevention among women is successful (Tuesday).
Finding harder and harder ways to do PMTCT seems to be a researcher obsession. A study demonstrated that women exposed to single-dose nevirapine during pregnancy responded better to lopinavir/ritonavir-containg regimens than to nevirapine-based ones. Thai studies demonstrated that treating the mother with AZT/didanosine or full ART for a month after exposure to single-dose nevirapine may stop the development of resistance. A cynic could argue that treating the mother's HIV properly in the first place with proper ART while she is pregnant would stop unnecessary use of protease inhibitors, as well as being better PMTCT (Tuesday).
MAMA, WHERE DID I COME FROM?
This was a hugely entertaining viral evolution talk on the origins of HIV--the speaker started with pylogenetic cacti!--ending up with the history of Kinshasa and ideas on ending the epidemic, using phylogenetic relationships between ancient HIV samples. He concluded that the emergence of HIV in the Congo was due to colonial activities and the creation of cities. This was more National Geographic than CROI, a kind of 'history of HIV in 25 minutes'. Did you know HIV was 'near extinction' at the turn of the 19th century? (Wednesday).
A viral pathogenesis update, from the droll Brit Daniel Douek, took the whole overview a step forward from the last time he presented 4 years ago (Monday). His final slide, melodramatically ending with 'when at the end, we are just left with (pregnant pause) ... the virus', made it more like bad science fiction than hard science. It was an excellent and simplified talk, walking us through the monkey models and the new understanding around the role of gut mucosa, understandable even to us clinicians. It is worth simply going to the last slide, and you will be on top of how the virus causes all this trouble.
For the brave or seriously geeky, the session late on Monday on 'Clues to lentiviral pathogenesis' was very good, especially Steve Deeks on elite controllers, and Sarah Rowland-Jones on the evolution of HIV-2. Deeks's talk was especially worrying, suggesting that even in those HIV-infected people who are lucky enough to be able to perfectly control their virus, there may be cardiovascular consequences--another blow for the 'hit early' treatment movement.
There were excellent overview talks on the Sunday before the conference, on all things basic science, and anybody wanting a solid grounding in the more arcane topics, such as host restriction factors and genomics, need look no further.
TUBERCULOSIS: NOT COUGHING UP ANY SOLUTIONS
A workshop just before the conference by STOP TB set the depressing tone for the TB prevention and treatment field. Elizabeth Corbett, in a comprehensive overview on Monday morning, discussed the issues around better TB control, with examples from community programmes such as the home-based testing programme in Uganda. Major prospects in TB care include two new tests for diagnosis, a new wonder drug (TMC207) and vaccine trials. The not-so-good news was the relationship between TB control and HIV treatment, the management outcomes of multidrug-resistant TB in high-prevalence settings, the emergence of more pathogenic strains in Cape Town, and poor infection control in Africa.
Durban's Professor Salim Abdool Karim presented his TB/ART data (we had a heads up when the data review committee stopped the trial in 2008), showing very high mortality in patients deferring ART till their TB treatment is completed. It is clear that we need to treat TB as a bit of an emergency in terms of getting people on to ART, even if their CD4 counts are in the previously supposed 'safe' zone of between 200 and 500 cells/[micro]l. Neil Martinson from PHRU presented a study that evaluated novel treatment for latent TB: rifapentin + isoniazid (INH) weekly, rifampicin + INH twice weekly, INH for 6 months and INH for the duration of study. There were no differences in the incident rate of TB in all arms; what was concerning was that the rifamycin-containing regimens seemed to select for drug-resistant TB. Continuous INH was protective against TB, but that effect dropped off soon after the treatment was stopped. In summary, TB was a serious downer for any clinician or patient or public health person. Luckily, we had Cape Town's Graeme Meintjes to cheer us up with his excellent 'Randomised placebo-controlled trial of prednisone for TB IRIS', which showed that early use of steroids, for 4 weeks, decreases the severity of disease due to TB IRIS with no significant side-effects.
PREVENTION GLIMMER OF HOPE
Much like TB, the HIV prevention field seems only to be facing worse data and negative trials. However, there was a flicker of hope, with the first positive biological prevention result since male circumcision. The much-anticipated HPTN035 microbicide results were presented by the ubiquitous Professor Karim, to much excitement amongst microbicidalists (and a little cynicism at the excitement in certain circles) (Monday). Microbicides are introduced into the vagina or rectum before sex, and kill the virus or stop it from entering the mucosa. Over 3 000 women enrolled and were randomised to one of two different microbicides, a placebo gel or no gel at all. Results showed that there was a 30% protection with use of the Pro2000 gel, but this was not statistically significant (the second gel, BufferGel, did not work). However, after separating out the patients who had a high rate of Pro2000 use (85% or more) and a low rate of condom use, there was a 78% reduction in HIV infection, which was statistically significant. It is not clear what this means, as much work still needs to be done before a trusted product can be released, but it was a healthy pick-me-up for a very bruised field. It has intensified excitement around a bigger microbicide study, with results due for release later this year.
Another tactic, pre-exposure prophylaxis (i.e. getting ART before a high-risk exposure, known as PrEP), got some support from animal studies, with a solid overview of the field by Sharon Hillier on Tuesday morning.
But the elephant in the room--whether ART is the most effective form of prevention--managed to raise some debate. The idea that lowering viral load decreases transmission risk has been around for a decade, but the tone of the debate dramatically increased last year, with the 'Swiss Statement' forcefully arguing that people on stable ART with undetectable viral loads were non-infectious, and a Lancet study, released last World AIDS Day and using a mathematical model, demonstrating that there would be a massive decrease in HIV prevalence if everyone found with HIV was given ART, irrespective of CD4 count. A study by Steven Reynolds in Uganda demonstrated again the dramatic reduction in infectivity, this time in sero-discordant couples in a cohort. Not a single transmission occurred in the couples where the HIV-positive partner was on ART; in the untreated cohort, the HIV incidence rate was 8.6/100 person-years, messing with all our preconceptions of what constitutes 'safer sex' (Monday).
THEM DRUGS FOR YOUR HEALTH AND HEART
Tenofovir is now first-line therapy in the state programme in Zambia, replacing stavudine (d4T) and zidovudine (AZT). Unsurprisingly, tenofovir worked well versus stavudine (although AZT did pretty well too) in Zambia in a large cohort, with very little renal trouble. Follow-up was short, and data unsurprising but reassuring (Wednesday).
There were more data on protease inhibitor monotherapy, which went through a vogue after promising preliminary results a few years ago. Data from the conference showed that patients don't suppress as well once they've been on triple treatment, if you switch to mono-boosted protease inhibitors. With all the new drugs available, it makes it hard to see how this approach can ever be justified, other than in highly selected patients (Tuesday).
The 'Prevention and treatment of serious OIs and malignancies' session on Monday was also very good. Patients in Uganda who stopped their co-trimoxazole because their CD4s improved on ART, got sick or died in huge numbers from malaria and diarrhoea, challenging guidelines that co-trimoxazole can safely be stopped in poorer or malaria areas.
Steve Lawn gave an interesting talk using Cape Town mortality data. He called the sub-200 CD4 count the 'death zone', showing chilling death rates. He asked 'Why do we only treat when people enter the death zone?', suggesting starting ART earlier rather than later. A study on longer-term outcomes from the productive ART-LINK consortium again showed the startling mortality if we treat at low CD4s. Treating late means that the health system deals with more sick patients, and that the ones who do get treated do worse. Lawn spoke of many countries in our region just doing 'firefighting'--treating the wave of sick patients, rather than heading off the sickness by treating them earlier, even if it meant greater medication expense (Monday, Wednesday).
A study demonstrated that HIV is an independent factor for atherosclerosis--as potent as smoking or diabetes, when looking at pre-clinical lesions. We have all suspected it, as evidence around the issue accumulates, but this was the starkest yet. The argument around starting ART at a higher CD4 count continues, as it seems that virus in blood = bad news for your arteries. One comment in the discussion--that HIV is much worse for the arteries than the relatively minor effects of the antiretrovirals--is an amazing acknowledgement of how far the field has moved in a few short years. Previously, the biggest concern involved the mild metabolic interruptions seen with the drugs; now, the major concern is around the inflammation caused by the virus (Monday).
The curious case of the controversial increased abacavir-induced myocardial infarction risk continued to unfold, with one study showing hypercoagulation linked with the drug, and another showing no increase in inflammation, in an attempt to explain the correlation observed in four studies and not seen in two others. Didanosine was also implicated in last year's report. The D:A:D study (Data Collection on Adverse Events of Anti-HIV Drugs) that caused all the original trouble around abacavir again looked at their database, confirmed the continuing link with abacavir and didanosine, and are now seeing a link with protease inhibitors indinavir (which thankfully is hardly used) and lopinavir/ritonavir (which is very commonly used in our region). Several other drugs, including the non-nucleosides nevirapine and efavirenz, were given a clean bill of health. A separate French study confirmed a link with abacavir and lopinavir/ritonavir, as well as with other protease inhibitors, but not with didanosine. The lesson for the clinician is to probably avoid abacavir, didanosine and lopinavir/ritonavir in high-risk patients for now, and focus on risk factors such as smoking, while these huge databases are followed for more conclusive data (Monday).
There was lots of worrying kidney stuff on Monday in the 'Pharmacogenetics, pharmacoenhancement, and complications of ART' session. It is clear that we are facing an HIV-induced renal epidemic on top of all the other complications of the virus.
The ongoing sad failure of prevention was starkly documented in a shocking presentation on rural KwaZulu-Tatal by the Africa Center, updating their data last presented in 2007. The study, looking at adult men and women at different ages, showed peak annual sero-incidences of 7.7% for women between the ages of 20 and 24, and 6.4% for men aged 25 - 29. The data have been collected serially since 2003, and the researchers showed that the new infection rate has not changed between 2003 and 2007 in any of the studied age groups, despite intensified prevention effort (Wednesday).
All the effort, energy and creativity that is going into treatment, prevention of long-term complications, new approaches to immune suppression and trying to mitigate the social consequences of AIDS, seems incredibly out of kilter when compared with the bleakness of the state of prevention research. The sheer scale of the short--and long-term consequences of the virus, in terms of the endothelium, metabolism and organs and the drain on social, economic and health resources, let alone the human consequence, means that a critical examination of HIV prevention research is desperately needed--now more than ever.
Dr Venter is supported by PEPFAR and grant NIH/ FIC 1U2RTW007373--01A1. Dr Osih is supported by PEPFAR.
Francois Venter, FCP (SA)
Regina Osih, MD, MPH
Reproductive Health and HIV Research Unit, University of the Witwatersrand, Johannesburg
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