CAPT Network News
Personal Reflections on the IAS Conference
(held in Cape Town, July 19 to 22, 2009)
By Dr. Jim Muller, Chief Physician
Pietermaritzburg Metropolitan Hospital Complex
IAS Cape Town took place at the Cape Town International Convention Centre in an unseasonably warm week in the middle of the winter. There was much sunshine and little rain. I was fortunate enough to be sponsored to attend the meeting by the CAPT Network.
AIDS has become a huge international industry now. There are numerous societies and numerous meetings. IAS seems to be one of the bigger organisations with a truly global reach that has developed out of this unprecedented pandemic of our era. As ever, there are many Americans involved, and there is much American money, but there are representatives from all parts of the world where the HIV virus is doing its work. For this meeting, the world came to Cape Town. On one evening during the meeting I had dinner with some Canadians who are supporting our research efforts in Pietermaritzburg. One member of the dinner party had been in Beijing two days before, and in Vancouver the day before; and seated at the table next to us was a drug rep from Japan. Now, thanks to eating out in Cape Town, I also know the difference between a crayfish and a langoustine.
Presented at the meeting in sessions and as posters were a huge array of studies and opinion pieces. There were studies from the developing world (“limited resource countries”); and studies from the developed world. They often put into stark perspective the difference in the size of the problem and the resources available to tackle it in these two worlds, but there is also no doubt that the two worlds need each other and can benefit from mutual co-operation and understanding. A huge amount of treatment and investigation, particularly in sub-Saharan Africa, is being funded by and carried out by people from the developed world, and whatever else you think about Mr Bush, his President’s Emergency Plan For AIDS Relief (PEPFAR) is head and shoulders above the rest in funding of prevention and treatment of HIV infection in Africa.
This report is a personal view of the conference. There is no way one person can glean all that is to be gleaned from a conference of this size with thousands of delegates and hundreds of presentations. One tries to identify sessions one can attend that will enhance one’s understanding and knowledge of treatment and prevention options. It is a hit and miss affair. Some of the sessions such as that by Rachel Jewkes on sexuality in southern Africa rang very true. At some of the sessions, such as one that I attended on something to do with laboratory parameters of the immunological response to the virus, the presenters might as well have been speaking Greek for all the understanding I had of what they were talking about.
In this report I am going to concentrate on the highlights from my perspective. If you want to know more, there are lots of ways you can access data from the conference on the internet, but if you want to do it quickly and effectively it helps to be a teenager. I am also not going to present the information in the order in which I acquired it at the conference, I am just going to present it any old how, starting with the things I really found fascinating and even “groundbreaking”.
First I want to talk about the “DART” study. This was done in Africa with first world money. The sites were in Uganda and Zimbabwe and it involved the treatment of over 3000 participants with triple ART regimens containing two NRTIs (AZT/3TC) and tenofovir. A few patients got abacavir or nevirapine instead of tenofovir. They were followed for five years. The study group had only “clinically driven monitoring” (CDM) and the control group had “laboratory and clinical monitoring” (LCM). The idea of the study was to see if places that cannot afford laboratory monitoring can still successfully treat patients with ART. The answer seems to be a resounding yes. Survival in the LCM group was 90% and in the CDM group it was 87%! By contrast the pre-treatment 5 year survival rate in the same communities was about 15%. The investigators conclude that you can run a fairly successful ART program with clinical monitoring as the mainstay of your patient follow-up and only do laboratory tests when they are clinically indicated, not as “routine screening”. The message to me is quite clear – if your resources are limited, expend them on getting pills into patients first and foremost. Secondly make a big effort to get everyone who ought to be on pills onto pills with the minimum possible delay. It is my impression that we are already following this advice in our communities within our cost constraints.
The DART study stimulated a lot of discussion in forums where experts were talking on their perspective of the “state of play” in the world with regard to ARV therapy. The idea that you could manage patients long term with very limited laboratory monitoring led to sometimes heated debate, particularly from physicians from the developed world (read the private sector in South Africa) who monitor their patients with many and frequent laboratory tests. The tests do give you some additional benefit in survival but the bulk of the survival benefit comes from the pills.
While I am on the topic of first world versus developing world strategies, I would also like to touch on the issue of D4T. There were some speakers calling for D4T to be banished into the wilderness of unacceptably toxic drugs immediately and forever, and for it to be replaced with tenofovir wherever it is being used. Unfortunately, as far as I know, D4T is currently the cheapest ARV drug on the market, and is still proving efficacious and tolerable to a large number of patients in the less resourced countries (LRCs). There just is not enough money out there to replace it all with tenofovir overnight. Word is that PEPFAR funding has been frozen (i.e. it is not increasing) for a couple of years due to the current economic crisis. Congressmen in Washington have to decide whether to borrow more money and add another couple of billion dollars to the national debt of the USA, to save jobs in the American auto industry, or to save lives of people living in Africa. If you are living in Africa, the choice may seem to be a “no-brainer” but when you are a congressman, your job depends on the votes of your constituents. While I was in Cape Town, I heard the Director of Medecins sans Frontieres (MSF) at Khayelitsha on the Cape Flats talking to a radio talk show host about antiretroviral therapy. He made the point that even in a middle income country like South Africa, patients in the public sector still have access to a maximum of 8 (eight) different ART drugs. In the developed world there are now 34 (thirty-four) drugs on the market! It is difficult not to interpret this as a gross injustice. However the silver lining to this particular cloud is that, unlike malaria, which does not occur to any extent in the developed world, HIV infection is still enough of a problem in developed countries for drug companies to put a lot of money into developing new drugs to treat it with. Some of these drugs are bad (D4T) and do not stand the test of time and will eventually disappear; most of them are good (such as efavirenz for example) and become cheaper as time passes. The challenge is to make them cheaper quicker, and there are plenty of lobby groups working on just that challenge. My own feeling about drugs is that they are not going to work forever, no matter how many new ones are developed. In the end there are only so many ways you can join atoms of carbon, oxygen, hydrogen, nitrogen and sulphur and a few other elements together before you run out of possibilities, and so the ultimate answer to the epidemic has to be to prevent the incidence of new infections – more of which later! I want to talk some more about treatment first.
Time not only sees the development of new drugs; it also sees the development of better and easier ways to use the drugs that we have. So regimens get simpler and easier to take. A particularly good example of this is a trial that was conducted in 32 centres across the length and breadth of France. The investigators took a little over 200 patients who were stable with undetectable viral loads for at least 18 months on triple therapy, and randomised them to darunavir plus two NRTIs (control group), or boosted darunavir on its own (study group). There were three failures in the monotherapy group, but they were all because of non-compliance. According to statistical analysis, monotherapy was “non-inferior”. The minimum time on monotherapy was 48 weeks. The implication of this is that if you have stable healthy patients with suppressed viral replication, you can put them on monotherapy and be fairly confident that they won’t “fail”. Obviously longer follow-up is needed to see if the viral load suppression is maintained for years rather than months, but it is difficult to see why it should not be. Another boost for monotherapy is that the CD4 count response was better in the monotherapy arm. So – monotherapy makes a comeback! This has huge implications. Imagine a future where millions of people in Africa can be maintained indefinitely on monotherapy boosted darunavir, or whatever else the drug companies and drug trialists dream up in the next few years. The relationship between the developed world and the developing world in this regard is like that between Michael Schumacher and the ordinary motorist. In the developed world new agents and new ideas can be easily developed and tried out. The ones that work can then be applied in as cost effective a manner as possible to the developing world (LRCs). This can be globalisation at its best!
Another trial looked at triple therapy with ABC/3TC and boosted atazanavir versus ABC/3TC with unboosted atazanavir. As hoped by the investigators, unboosted atazanavir was no less effective, but less toxic than boosted atazanavir. This was particularly true of lipid levels which were significantly less in the unboosted arm. Thus do we gradually find out how to administer effective therapy and cause our patients as little harm as possible.
In the Wednesday Plenary sessions, Pedro Cahn from Argentina looked at the history and future of ART therapy. In the first five years from 1996 to 2001 the emphasis was on stopping and reversing the failure of the patients’ immune systems. In the next five years from 2002 to 2007 the emphasis was on maintaining viral load suppression at less than 50 copies to prevent the emergence of resistant strains of virus. Now the emphasis is on diminishing the non-AIDS morbidity and mortality, and on preventing virus transmission. Professor Cahn had no doubt that D4T should go because of unacceptable short and long term toxicity. D4T selects for K65R in clade C viruses. This may lead to the spread of K65R in viruses in southern Africa and a public health disaster – another reason for doing away with D4T. He also stated that viral load testing is essential to preserve drug efficacy. Many patients who are “switched” on grounds of clinical deterioration and lower CD4 counts in fact still have adequately suppressed viral loads (he put the figure as high as 50%). There is no evidence to support any particular strategy when it comes to switching. The work still needs to be done, so at the moment all practitioners base their decisions to switch on theoretical considerations but usually on obvious “failure” with higher viral loads. Viral loads need to be made available more cheaply and reliably in all settings to be used as evidence in decisions to switch patients (the “tie-breaker”). Viral loads can also be used to monitor adherence, as I discovered recently in one of my own patients. They should probably not be used for “routine” laboratory monitoring. The same is true of CD4 counts. They should only be used to decide about initiation of therapy. After that it is felt that their role is limited.
This brings us to another trend in therapy, and that is to starting ART earlier and earlier. Those of you who have been around for a while will recall that when HAART was first introduced it was suggested that it should be given to patients from the outset of their HIV infection regardless of their CD4 count. Then the pendulum swung the other way because of the toxicity of ART. So we got to the cut-off of 200 CD4 cells. The WHO now recommends that treatment be started at a CD4 count of 350, but the rule in South Africa is still 200. In Uganda it is 250. According to Professor Cahn, starting ART late is bad for the patient and good for the virus – it encourages the emergence of resistant strains of virus. Patients who start at 200 are 4 times more likely to die than patients who start at 350. Where does this leave us in South Africa, and indeed in Pietermaritzburg? We are still struggling to get all our patients under 200, and indeed under 50, onto ART. Extending the cut-off to 350 at this stage would probably deny therapy to a lot of desperately ill people to the benefit of a lot of well people. Personally I don’t think we are ready for 350 yet. The trend in the developed world is now again to start therapy earlier and earlier because the new drugs are less and less toxic, and because there is more and more evidence that by delaying therapy, the virus can do damage to the patient (for example to the CNS, and indeed to the immune system) which may not all be reversible when therapy is eventually started.
I would like at this stage to create some perspective on the situation in Pietermaritzburg. The district of Umgungundlovu has a population which is just under a million people. The ART program in our government hospitals and clinics (now) has already started more than 30 000 people (3% of the population) on ART since the inception of the program in 2004. I guess that we will have to put an additional 30 000 on treatment before we have “broken the back” of the problem of the under 200s. If we then start with under 350s, that will probably mean enrolling another 30 000 people. So the number of people on treatment, assuming a drop-out rate of 10% or so, would be about 80 000 (8% of the population of the district) on an ongoing basis. Now if we have 20 clinics in the district, that will mean that every clinic will be carrying 4000 patients on chronic ART therapy. So they will have to see 1000 patients every week or 200 patients every day to keep them on their ARTs. And that is only to issue their ARTs once a month and not if they have any clinical problems. Clearly this is not sustainable and argues strongly for issuing patients with drugs for 3 to 6 months at a time if they are well and stable on treatment. It also argues strongly for simplifying the ART regimen so that patients are not disinclined to take it because of its toxicity or complexity. Fortunately for us, Professor Cahn sees some remarkable new drugs in the pipeline. The integrase inhibitors raltegravir and elvitegravir are seen by him as “stars” of the present. New classes of drugs are coming along (maturation inhibitors) – so altogether there is a steady improvement in the quantity and quality of new drugs.
Let’s go back to the situation on the ground in our communities. We know that about 40% of pregnant women who attend antenatal clinics in government hospitals in our communities are HIV positive. This means that all these people who currently are “asymptomatic carriers” are going to progress eventually to lower CD4 counts and need to go onto ART. The above scenario of 8% of the population of the district being on ART was assuming no change to the current prevalence of low CD4 counts. In reality that 8% is going to go on climbing indefinitely unless something is done to stop the spread of the virus to the uninfected population. This is where Rachel Jewkes comes in.
Why does southern Africa have the worst HIV epidemic in the world?
Rachel Jewkes is the Director of the MRC’s Gender and Health Research Unit in Tshwane. She is a specialist in Public Health and has spent the last 15 years undertaking research into gender and sexuality issues in South Africa. She did a presentation at the Wednesday plenary, and it is her perspective that we need, both to understand the underlying causes of the rampant HIV epidemic in our communities, and to find effective ways of dealing with the spread of the virus. From Dr Jewkes’ investigations it seems that the root cause of the epidemic in South Africa is the way that men and women relate to each other sexually in our communities. This may seem like a very obvious thing to say, but it does need to be recognised and it needs to be recognised as a problem before something can be done to change it (vide Dr Phil). First a myth needs to be debunked, and that is the myth that the reason for the very high incidence of HIV infection in South Africa is rape. According to Dr Jewkes, although rape is a huge problem in South Africa, its contribution to the HIV epidemic is relatively insubstantial (probably far less than 1% of the total incidence). What emerges from Dr Jewkes research is that what puts South African women at risk of HIV infection is sexual and intimate partner violence. According to Dr Jewkes, in anonymous question sessions to men at random in our society, it emerges that 28% of men have raped, 42% of men have perpetrated partner violence, and 80% of men have participated in transactional sex. The theory of masculinity which describes this set of circumstances is called “hegemonic masculinity” and it entails men having multiple partners as a norm. It entails women being subservient to men as a norm, and women being complicit in men having multiple sexual partners as a norm. In antenatal clinics in Soweto, women who report one incident of inter-partner violence are 50% more likely to be HIV positive, as are women who report a “power inequity” in their relationship with their man. To put the problem in a nutshell it is that men who have multiple partners are desired by women and envied by other men. Dr Jewkes says that there are also barriers to men entering the health care system, which tends to be organised around the needs of women and children. The message really does need to go out that having multiple partners may be cool, but it is very dangerous. Perhaps our politicians could take the first step in this direction??
This being a meeting in Africa about HIV infection, it was inevitable that there would be presentations about tuberculosis (TB). Gerry Friedland talked about the epidemic of XDR TB at Church of Scotland Hospital on our own doorstep, and what had been learnt from it. It appears that the XDR strain was spread in the hospital wards and that very basic infection control measures can be applied and are leading to a decline in the incidence of XDR TB in the Msinga community. These measures include early case finding, keeping patients in the community and out of hospital, and simple infection control measures (keeping the windows open). Dr Friedland also coined the phrase “treatment trumps stigma” – a useful thought, and one to convey to one’s patients.
Karen Middelkoop from Cape Town demonstrated a remarkable drop in the incidence of TB in a community after the introduction of ART. 25% of the population in the community are taking ART. TB prevalence has dropped from 3% in 2005 to 1.8% in 2008. Thus it seems ART protects from TB.
TB was another “orphan” disease for a long time as far as the drug companies were concerned, because the TB epidemic in developed countries was essentially terminated before the Second World War, so there was no real incentive to develop new treatments or vaccines. HIV has changed all that, as has massive migration of immigrants from LRCs to the developed countries of the world. These people take their latent TB disease with them and then get active TB disease when they get old or sick (or immunosuppressed). BCG has been around as the only “vaccine” for TB for nearly a century (since 1921). It is inefficacious and in some instances dangerous. It appears that a good deal of work has been going on recently to develop totally new vaccines against TB. This was related to us by Dr Jerald Sadoff of the Aeros Global TB Vaccine Foundation. He told us that a number of new BCGs are on trial in Africa and that they promise to be safer and more efficacious. There is also a new experimental vaccine which is administered by inhalation. Dr Sadoff has 4 vaccine trials under way now and expects two more in 2010. One of his trials is in Worcester in the Western Cape. Dr Sadoff is very hopeful that there will be an effective vaccine for TB available for wide use in the general population within the decade. This is very good news, as it is TB that kills most people with HIV infection in Africa.
At the opening ceremony, Mr Kgalema Motlanthe, South Africa’s Deputy President, gave a speech on the government’s goals for the campaign against HIV. This was after Julio Montaner, the President of the IAS, said that the goal of the IAS was universal coverage, based on a CD4 count of 200, by 2010. This means adding 6 or 7 million people to the 3 million currently on treatment. The South African government’s goals are a bit more modest, but probably more realistic. They want to put 80% of those in need on treatment by 2011, and to achieve a 50% decline in incidence of new infections by 2011. I think the former goal may be attainable, but personally I am sceptical that the other can be achieved without a Museveni type campaign of sexual truth across the whole community.
I must confess to not having spent much time at discussions about vaccines in the conference, because I am personally sceptical about the development of an effective preventative vaccine for this virus anytime soon, if ever. What I think holds much more promise is the mantra “treatment as prevention”. Although there is little evidence to date to support the idea that spread of infection in the community will be limited if all viral loads are below 50, there is compelling theoretical evidence to support this idea, and trials are under way in some locations to provide hard evidence. One such trial is being conducted in Uganda, by David Moore of the CAPT Network. If all infected people are on ART and they all have viral loads below 50 then the risk of transmission to new uninfected people should theoretically become minimal. Perhaps this is how the epidemic will eventually be defeated. This does not mean to say that treatment as prevention can be substituted for behaviour change. They need to be promoted together. The goal of proving that treatment can prevent spread is to then persuade donor countries to make available more resources so that all those with detectable viral loads can eventually be put on treatment regardless of their CD4 counts. This is a tall order, but may prove necessary in the end.
A session attended but not reported on was on PMTCT. Here there is still a long way to go in achieving the sort of penetration of ART that is needed to effectively prevent MTCT.
Bruce Walker talked about how some people manage to control the virus on their own without ART. He is trying to develop an understanding of how this is achieved by the long term non-progressors to see if other people’s immune systems can be persuaded to control the virus in the same way.
No HIV conference in Africa would be complete in 2009 without a mention of circumcision as prevention. All one needs to say is that it works.
Pregnant women are particularly at risk from HIV and malaria. HIV infection increases the risk of severe malaria and death about tenfold. As well as HIV making malaria worse, malaria makes HIV worse. HIV patients being treated for malaria have an increased mass of malaria parasites because of a failure of innate immunity to the parasites. This exposes them to greater risk of developing resistance to antimalarials. Artemisinins are thankfully still effective in malaria in Africa. They also may have some antiviral activity. Co-trimoxazole also decreases the risk of malaria, but this does not mean that standard preventive measures such as residual spraying and insecticide impregnated bed nets should not be applied.
Only a few selected types of cancer have a particularly elevated relative risk in HIV infection. Of course we all know NHL and KS which have relative risks in the hundreds in HIV infection. HL has a relative risk of about 10, and anal cancer has a relative risk of about 40. We of course also know about cervical cancer and HIV in Africa. Reducing the viral load and increasing the CD4 count with ART does decrease the risk of cancer, but not back to normal for these cancers.
Another theme of the conference was the concern about chronic degenerative conditions and HIV infection and ART. Now that more people are surviving much longer on ART, these chronic conditions are coming to the forefront of the difficulties that HIV clinicians have to deal with in their patients. There is room for watchful expectancy and early and sometimes preventive intervention with some of these problems.
Bone mineral density declines from the outset of HIV infection in much the same way that it does at menopause. Treatment with PIs and some nucleosides makes matters worse. It is recommended that patients with HIV infection be screened for BMD decline and that those that qualify according to the FRAX score should have BMD measured and then be treated with bisphosphonates if indicated. Attention should be given to optimising vitamin D and calcium intake in all patients with HIV infection. Although are not universal in patients on ART they are common. The solution for now appears to be to screen early and vigorously for atherosclerotic risk factors and to intervene when indicated with lipid lowering therapy. It may be necessary to “switch” because of intolerable lipid derangements and atherosclerosis. Fortunately the newer ART agents that are coming into use more frequently now in the developed world appear to have less in the way of side effects in this regard.
HIV establishes itself in cells in the central nervous system early in the course of infection. It attracts immune competent cells across the blood brain barrier and this leads to damage to neurological tissue. These phenomena are referred to collectively as HIV Associated Neuro-cognitive Disorder (HAND). The ALERT study looked at 1200 people with HIV infection not on ART. 39% of them had subtle impairment of neuro-cognitive function at the first visit. Later the majority improved on ART. The efficacy of ART in the CNS depends on the ability of ART agents to penetrate into the CNS. NRTIs are better than NNRTIs which are better than PIs. Some of the newer drugs like raltegravir, darunavir and maraviroc may penetrate the CNS very well. The CNS may be a reservoir for virus which facilitates the development of resistant strains because of the variability of drug penetration. HAND may have deleterious effects on activities of daily living and employability.
Attending the IAS Cape Town conference was both a privilege and a pleasure. As ever at such gatherings there was much to give one hope and much to give one pause for thought and some things even to make one a bit trepid, if that is possible. The HIV/AIDS bandwagon rolls on and many if not most of our patients benefit in the end.
Dr Jim Muller
Chief Physician Pietermaritzburg
