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Metabolic Complications of HIV infection
Update form the 5th IAS Conference in Cape Town
- Pablo Tebas MD, University of Pennsylvania
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The 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2009) took place in Cape Town, South Africa between July 19th and the 22nd of 2009. The event is organized by the IAS, in partnership with South African-based NGO, Dira Sengwe.
This conference, which alternates with the International AIDS conference every other year, is smaller in size and more focused on the scientific aspects of the HIV infection than the International AIDS Conference, which took place in Mexico City last summer and will be in Vienna next year. The last of these International AIDS Conferences in the US was in 1990 in San Francisco California. Since then they have been boycotted in protest of a law that was passed in 1987 that restricted access to the US to patients living with HIV. It has taken more than 20 years for that legislation to be repealed. Last year WECA103, 2009. our US Congress voted to repeal the 1987 restrictions on HIV-positive immigrants as part of a package of AIDS reforms proposed by President George W. Bush (although I am not a fan of GW, "give Caesar what belongs to Caesar"). The Obama administration hopefully will take the last steps in repealing this absurd law. Many of us hope that this will mean the return of this conference to the US, which will provide a symbolic gesture of the return of the US to regular club of nations that do not restrict the access to patients living with HIV infection. The CDC is seeking public comment on the new normative till August and then the foolishness of this rule will finally be over.
This was a very well organized conference with some important presentations that have the potential of changing practices across the globe. I will mention briefly them, although they will not be the focus of this article, as they will be discussed by others. The most important study was the CIPRA HT 101 , presented by Fitzgerald et al. 1 that demonstrated that starting therapy between 200 and 350 CD4 cells/mm3 not only decreases the incidence of tuberculosis, but also death. This study settles the issue of when to start antiretroviral therapy in the developing world -when the CD4 is below 350- and moves the question to how international and domestic programs across the globe are going to implement that new recommendation in the middle of the economic recession that we have now. Starting therapy earlier is probably even more important in the developing world than in developed countries because HIV positive individuals do not have the cushion of a reasonable Health system. The other two studies that I think were very important are: 1) the Mma Bana study from Botswana 2 that showed that giving HAART to the mother during breastfeeding can decrease the incidence of HIV in the baby to very low levels (1%), similar to the numbers we are accustomed to in the developed world. 2) the BAN study3 from Malawi that showed that by giving nevirapine to the breastfeeding baby (and not necessarily treating the mother, can reduce transmission to 2%. This strategy is easier to implement, as the cost is clearly smaller than the Mma Bana approach.
The conference was framed by two impressive speakers. The first day the former president of South Africa, and current Deputy President, took the podium. Kgalema Petrus Motlanthe was president for a few months after Mbeki left power during the fall of 2008, and until the new president Zuma took over in May of 2009. Motlanthe, like Mandela, was a prisoner in Roben Island, only a few miles from the Conference Center and a reminder to all of us of the dark years of apartheid in this beautiful country. In contrast with his predecessor that during the first years of presidency gave an ear to some HIV denialists, Molanthe from the beginning, wanted to address the problem of HIV in South Africa from a scientific perspective. His speech was moving and political, as expected in these meetings. The last day of the conference, Nelson Mandela's wife, Graca Machel, an activist for women's and children's rights, took the podium and gave an impassioned speech asking the developing world and the G8 to live to their commitments and to African governments to take care of their citizens. Her speech was one of the highlights of the conference from the political point of view.
Lets get back to business. I will focus in what I thought were the most important metabolic presentations of the meeting. As expected the session about metabolic complications was over taken by presentations related to the presumed increased risk of MI after abacavir use that have dominated these discussions for the last 18 months.
Dominique Costagliola, the lead investigator of the French ANRS CO4 study, presented last February in CROI, was asked to summarize the state of the knowledge regarding abacavir and cardiovascular risk4. Her presentation was a real shocker, as she was very, very critical about the evidence that sustain that abacavir use is associated with increased cardiovascular risk. If you remember, Dominque Costagliola presented data from the ANRS that seemed to confirm to some degree the association of abacavir and MI. This time she basically said that her original data did not show an association between abacavir and MIs, that it looked that there was an association because they sliced the data further after they found no association between abacavir and MIs only because DAD had suggested that there was an association, and that she believes that there are reasons why people chose abacavir over tenofovir that give the appearance of an increased CVD risk when using abacavir. It really sounded like a retraction, and I think everybody was surprised. Although she did not explain clearly the reasons behind her change in position, it seems that on further analysis of the French cohort study, if IVDU (intravenous drug use) was controlled, there was no association of abacavir and MI... It is well known that IVDU, particularly cocaine, is associated with cardiovascular risk. So the association that they observed in the ANRS study may be explained by intravenous drug use. For reasons that I do not quite get, if you are an IVDU in France you are more likely to receive abacavir than if you are not. (from Jules: she told me when they eliminated patients with current cocaine use & IVDU from the analysis of the database abacavir was no longer associated with MIs). Another of her comments focused on the role that ongoing HIV viremia has in cardiovascular events.
Then, Roger Bedimo presented data from the VA cohort5, a large observational cohort with more than 19000 patients and 278 myocardial infarctions. In this study there was no clear association between abacavir use and MI (cumulative use). In a non adjusted statistical analysis the use of abacavir was associated with a marginally (non) significant increased risk of heart attack (hazard ratio [HR] 1.27, or 27% increased risk). However, after adjusting for chronic kidney disease, the main reason why clinicians use abacavir over tenofovir the association attenuated and became non significant. The association attenuated even further after controlling for traditional heart disease risk factors. The study also pointed out that abacavir was more likely used in individuals with chronic kidney disease, and that chronic kidney disease was associated with myocardial infarction
These two presentations clearly showed the main problem of observational cohorts: their inability to control for unknown bias that "drift" the use of a particular drug to a particular population, that may be associated with a particular outcome and at the end gives the impression that the drug is associated with that particular event. Clinicians and researchers should look at observational cohorts with extreme care, as it is very easy to reach the wrong conclusion. As an example, DAD published in the year 2007 that being on antiretroviral therapy (particularly protease inhibitors) was a risk factor to have a myocardial infarction, however we know that stopping antiretroviral therapy increases your cardivovascular risk. Looking at the original data you would think that stopping therapy should be a good thing regarding cardiovascular risk, and the SMART study was based in part on the assumption that the use of antiretroviral therapy was associated with significant metabolic toxicities, so that it would be reasonable to try to minimize total drug exposure, however stopping therapy was clearly not the answer to the problem of metabolic toxicities associated with ART treatment. Things are much more complicated than that.
There was a poster from the Quebec cohort that presented evidence that seemed to corroborate DAD observations regarding abacavir and MI risk6. In that study, 125 MIs in HIV infected patients were matched with 1084 controls. The use abacavir, didanosine, stavudine, zalcitabine and PIs lopinavir and ritonavir associated with increase in MI risk. The study did not control for chronic kidney disease and attempted to control for traditional risk factors by looking at the concomitant use of treatment drugs like antihypertensive, antidiabetic, lipid lowering or antiplatelet medications. No other more robust attempts to control bias were included in this study.
Causality is a complicated business and requires more than a statistical association. Sir Bradford Hill, a British mathematician, outlined many years ago the minimal conditions needed to establish a causal relationship between two things. They include the strength of the association, the consistency, the specificity, the temporality, the biological plausibility, the dose response, experiment and analogy. A full discussion of these criteria is beyond the scope of this review, but my point is that if any clinician or researcher reviews critically the evidence linking abacavir use to myocardial infarctions, it is clear the evidence has not proven causality yet, and may never be able to do so.
If abacavir is associated with MIs, the next step is to find out what is the biological mechanism; what is the biological plausible explanation that would justify this increased risk? The evidence presented so far has not been consistent in this regard either. During the meeting a secondary analysis of the BICOMBO study was presented that tried to address the biological plausibility question. In this study individuals with well controlled viral replication were randomized to switch to an abacavir containing regimen or a tenofovir containing regimen. Esteban Martinez et al. 7 looked at changes in markers of inflammation, glucose metabolism and coagulation ( C-reactive protein, monocyte chemottractant protein-1, osteoprotegrin, adiponectin, IL-6, IL-10, tumor necrosis factor-alpha, ICAM-1, VCAM-1, selectin E and P, D-dimer, and insulin) and showed no difference between the arms (or within the arms). The study is small and somewhat underpowered to provide the final answer, but definitely does not suggest that there is a clear mechanism to explain the presumed increased cardiovascular risk associated with abacavir use.
There were other interesting "metabolically related" studies that cached my eye that fortunately were outside the abacavir wars:
Low vitamin D levels are extremely common among HIV positive individuals and the general population. In a study of 1007 patients from England8, the prevalence of very low levels of vitamin D was very high (35%) and was associated with black race, use of NNRTIs, evaluation during winter time and low CD4 count. Remember that association does not mean causation, so NNRTI use does not necessarily is the cause of low vitamin D...The study is important because it contributes a large, diverse cohort, to the well known evidence at this point that the presence of hypovitaminosis D is extremely frequent in the HIV infected population.
Another important study looked at the prevalence of low bone mineral density among participants of ART as prevention trials in Botswana(PrEP trials)9. Most of the currently ongoing trials of pre-exposure prophylaxis use tenofovir as the main component of the intervention. Little is known about the bone effects of tenofovir in a healthy, HIV negative population, or for that matter, the frequency of osteopoenia and osteoporosis among Africans. The study showed a low BMD in ≥1 anatomic site in 123 (57%) of the participants, which should bring a word of caution to these trials and its future implementation. However, it was not clear to me what was the standard population they were using to obtain the T scores. If they were using a North American population (as it looks like they did) , that may not be completely adequate and can profoundly affect the results of this study
There have been several promising studies suggesting that the use of uridine in patients with lipoatrophy 10-11 can quickly reverse it. The way that uridine works is by replenishing the nucleoside reservoirs that have been "depleted" by the continuous use of thymidine analogs. Uridine theoretically should work better if the patient is receiving thymidine analogs (ZDV or D4T), something that is not very likely anymore, as several studies have demonstrated that discontinuing the use of thymidine analogs improves subcutaneous fat. A. Calmy and the group of Andrew Carr in Australia conducted a small randomized trial evaluating the use of uridine, alone or in combination with pravastatin in patients with lipoatrophy that have discontinued the use of thymidine analogs. They were unable to demonstrate a consistent effect of uridine, pravastatin or both in subcutaneous fat in this particular population. The final answer to the utility of uridine, if any, for lipoatrophy will come from a large, ongoing ACTG study (ACTG A5229, clinical trials.gov # NCT00307164), that I hope will be presented soon. Dr. Rao and Mulligan form San Francisco are also conducting a smaller study evaluating escalating doses of uridine (clinical trials.gov #NCT00471614), that might also provide some light on this issue.
I just want to end stating that this was a great conference, perfectly organized, with some ground breaking presentations that made the trip to this beautiful country well worthwhile from the scientific perspective.
Bibliography
1. Daniel Fitzgerald et al. When to start ART in developing countries . Program and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract WESY201
2. Shapiro R et al. A randomized trial comparing highly active antiretroviral therapy regimens for virologic efficacy and the prevention of mother-to-child transmission among breastfeeding women in Botswana (The Mma Bana Study). Program and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract WeLLB101
3. Chasela C, Hudgens M, Jamieson D, et al. Both maternal HAART and daily infant nevirapine (NVP) are effective in reducing HIV-1 transmission during breastfeeding in a randomized trial in Malawi: 28 week results of the Breastfeeding, Antiretroviral and Nutrition (BAN) study. Program and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract WELBC103.
4. Dominique Costagliola. The current debate on abacavir; risks and relationship between HIV viremia and cardiovascular events. Program and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Presentation MOAB201
5. Bedimo R et al. Abacavir use and risk of acute myocardial infarction and cerebrovascular disease in the HAART era. Program and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract MoAb202.
6. Durand M, Sheehy O, Baril JG, Lelorier J, Tremblay C. Relation between use of nucleosidic reverse transcriptase inhibitors (NRTI) and risk of myocardial infarction (MI): a nested case control study using Quebec's public health insurance database (QPHID). Program and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract TUPEB175.
7. Martinez E et al. No evidence for recent abacavir/lamivudine use in promoting inflammation, endothelial dysfunction, hypercoagulability, or insulin resistance in virologically suppressed HIV-infected patients: a substudy of the BICOMBO randomized clinical trial (ISRCTN61891868). Program and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract MoAb203.
8. Welz T, Childs K, Ibrahim F, Poulton M, Post F. Efavirenz use is associated with severe vitamin D deficiency in a large, ethnically diverse urban UK cohort. Program and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract TUPEB186.
9. Bone mineral density (BMD) in a population of healthy HIV-negative young African adults enrolling in a pre-exposure prophylaxis (PrEP) trial in Botswana. Program and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract WECA103.
10. Walker UA, Venhoff N. Uridine in the prevention and treatment of NRTI-related mitochondrial toxicity. Antivir Ther. 2005;10 Suppl 2:M117-23. Review.
11. Walker UA, Langmann P, Miehle N, Zilly M, Klinker H, Petschner F. Beneficial effects of oral uridine in mitochondrial toxicity. AIDS. 2004 Apr 30;18(7):1085-6.
12. A. Calmy, M. Bloch, H. Wand et al. No effect of uridine or pravastatin for HIV lipoatrophy in men who have ceased thymidine nucleoside analogue therapy: a randomized trial. Program and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract TUPEB169
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