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Complications of HIV and its treatment, Impressions from the 20th CROI
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Pablo Tebas, MD
University of Pennsylvania
The second cure
The biggest story of the conference on retrovirus and opportunistic infections that took place in Atlanta was the story of a baby that was cured of HIV infection (1). The baby was born in Mississippi from a mother that didn't have HIV care during pregnancy. Immediately after birth two different viral loads were obtained and the baby was started on triple therapy (initially AZT/3TC/NVP and subsequently AZT/3TC/Lopinavir/r. The baby had an HIV viral load in the 20,000 copies/ml range, and quickly became undetectable. The baby continued the treatment for at least 18 months, then her mother was lost to follow up and decided to discontinue the treatment on her own. A few months later, when the baby returned to care, the HIV viral load remained negative and there was no evidence of ongoing replication or infection with HIV. The baby has been followed for several months off therapy without evidence of the virus returning.
This aggressive treatment probably worked because the baby was very recently infected, and did not have a chance to establish a significant reservoir, and because of that the antiretroviral treatment was capable of clearing the infection. The amount of memory T cells in a newborn is very small, and those cells constitute the best characterized HIV reservoir.
Some people think that because there was no reservoir, there was really no infection, and that the case basically constitutes a successful post-exposure prophylaxis. I disagree. I think this baby was infected, as there was evidence of ongoing viral replication in the blood, and that is the definition of infection. That is the way all infections are defined. Making the requirement for infection the establishment of a reservoir simply absurd. It is like saying that because hepatitis C infection does not establishes a reservoir; patients with hepatitis C are not really infected. Making this type of specific requirement will basically imply that we have to have a unique definition for "infection" for each different organism humans get infected with.
So I think this constitutes the second well demonstrated case of cure, and has tremendous implications for the care of newborns and even for patients with established infections as it clearly points out that if we could get rid of the reservoir, or protect it from reestablishment after a particular intervention, antiretrovirals alone may be able to eliminate the virus.
Some people linked the timing of this report to the re-competition of the HIV networks, including the pediatric network, whose future had been questioned. It is obvious now that we need to do more studies to evaluate what happened to this young girl. I think the suggestion that this was timed on purpose is plain meanness and I would tell them what Welch told McCarhy in 1954: Have You No Sense of Decency, Sir?
It is clear that this report has to be confirmed in subsequent studies, and those studies need to be started quickly. These studies will aggressively treat newborns with triple antiretroviral therapy immediately after birth, and if infection is confirmed maintain this treatment for at least a year, and then discontinue it and see how many children can be cured with that strategy. These studies will have to be done in Africa because in the United States there are not enough positive infected Children. If the case is confirmed it will have a dramatic impact on the goal of eliminating HIV from children.
Many years ago pediatricians thought that universal testing and treating works to prevent HIV infection (that is basically what we do during pregnancy, we test all women, treat all the positive and that decreases the risk of HIV infection). Maybe they will show us the way to eradicate HIV infection: do not allow the reservoir to be established (or if established get rid of it) and treat aggressively.
Neurocognitive impairment
Some studies suggest that patients with HIV infection, despite virological control, have ongoing neurocognitive impairment. Although this impairment is mild, and can only be detected using sophisticated neurocognitive testing, it creates great concern among investigators in patients with HIV infection. The presence of this problem led to the hypothesis that this neurocognitive impairment could be prevented by using drugs that penetrate the central nervous system. Dr. Letendre of San Diego created a system that scored HIV drugs according to their penetration in the CNS. He postulated that treatments with better CNS scores would be better in preventing the development of neurocognitive impairment.
Two studies were presented during these meetings that were testing this hypothesis in different ways. In the first study, presented by Ron Ellis, individuals that were starting a new antiretroviral regimen were randomized to a regimen with good CNS penetration and compared to patients that were randomized to a not CNS targeted regimen (2). The study was a small (it had difficulties with enrollment and it took almost 4 years to enroll 59 patients). The selection of CNS targeted regimen did not make a difference at 16 weeks, either in sophisticated neurocognitive testing or in biological outcomes in the CSF. In fact 87% of the patients randomized to a non-CNS targeted regimen reached virological suppression in the CSF, versus 68% of those receiving a CNS targeted regimen. The main limitation of the study is that the primary endpoint was taken relatively early, only after 16 weeks of therapy, and that a more prolonged treatment might be needed to see an effect. However, I think the study clearly shows that it is probably not the case that an antiretroviral drug has to penetrate the CSF to be able to exert a beneficial effect in brain function.
The second study (3), the PICASSO study, evaluated the neurocognitive evolution of participants of a trial in which patients were randomized to maintain boosted darunavir monotherapy or lopinavir/r or a combination of two nucleoside analogues with the boosted protease inhibitor. Darunavir/ritonavir & lopinavir/r do not have CNS penetration, so the hypothesis was that those patients whose treatment do not penetrate well the CSF should have some neurocognitive deterioration as a consequence. It did not happen, putting another hole in the theory that CNS penetration matters clinically. Another study showed that mega HAART did not improve the neuropsychological performance compared to stand on antiretroviral therapy in patients recently infected with HIV infection.
It was really a very bad year for penetration-effectiveness scores (CPE).
I think the combination these studies suggest that the most important thing to improve the neurocognitive situation of our patients is to give a fully suppressive antiretroviral regimen. It does not seem that selecting a regimen based on its ability to penetrate the brain has any additional benefit. I think it is going to be very difficult to pursue this idea in the future. If there is neurocognitive impairment associated with HIV infection in patients fully suppressed then it is going to be necessary to understand clearly the mechanism rather than targeting the HIV virus itself.
Statin Use
Patients with well controlled HIV infection on antiretroviral therapy have higher levels of inflammation than HIV uninfected individuals, these higher levels of inflammation have been linked to the outcomes including high cardiovascular risk, neurocognitive impairment, osteopenia and osteoporosis and increase risk of cancers.
Many small studies have tried to understand the mechanisms of these increased levels of inflammation. Some have proposed that low level viremia is a reason why patients maintain this inflammatory state. However studies that have tried to intensify antiretroviral therapy have shown disappointing results: intensification with maraviroc (4) or raltegravir (5) did not show that there was any clinically significant improvement in markers of inflammation with the addition of antiretroviral drugs to an already successful antiretroviral regimen. Other studies have suggested that the presence of CMV infection could be a contributor to this problem. A small study (6) of patients with fully suppressed viral replication randomized the participants to receive valganciclovir (a drug with activity against CMV) or placebo. The study demonstrated a small improvement in the levels of inflammation, but the regimen was poorly tolerated, and has a significant amount of toxicity, questioning the clinical utility of this type of intervention
We need practical and safe interventions to deal with the issue of ongoing inflammation in patients with HIV infection that can be safely implemented in the vast majority of the patients. The ultimate goal is to decrease inflammation and potentially prevent the development of complications associated with it. This will require large randomized trials, but in the current fiscal environment those studies would not be feasible.
Statins have been evaluated in the non-HIV infected population for this particular indication, and the Jupiter trial, published a few years ago in the NEJM (7), demonstrated an improvement in cardiovascular events in patients with high C-reactive protein that were randomized to receive rosuvastatin, a modern statin vs placebo. Three is simply no appetite for this type of study at the NIH targeting patients with HIV infection, which would be the only group with the capability to fund a study of these characteristics. So we have to accept the evidence derived from retrospective cohorts.
The problem of these retrospective studies is that it is necessary to do a lot of statistical tweaking to prevent bias. Patients that receive statins do so for a reason (they may have high lipids, chronic kidney disease, diabetes etc, and maybe other things that predispose them to have more cardiovascular events
Two interesting studies (8-9) were presented that demonstrated that the use of statins in patients with HIV infection (which in most cases is well controlled nowadays) decrease in mortality after correcting for potential confounders. One study was done in Denmark (9) and the other one in the VA cohort (8). Both showed consistent results with modest decreases in mortality in patients that were receiving a statin. Is this enough evidence to change our practice?, Should we give a statin to every patient with HIV infection? The answer is probably not (yet), but I also think that the trend is in the right direction, particularly in populations of HIV-infected patients that are at higher risk of having this "proinflamatory state": particularly patients older than 50 years, and those who started antiretroviral therapy with a lower nadir.
I would like to point out that statin therapy is not the panacea: two studies (10-11) demonstrated a small but significant increase in the risk of incident diabetes mellitus in patients receiving a statin, a trend that has also been observed in the general population. I think this data does not preclude the use of statins when they are indicated, but suggest that one should be cautious and monitor patients receiving these drugs periodically for the development of this rare, but real complication.
Aging
A few years ago, news that patients with HIV infection were aging rapidly made it into the main stream media and was a matter of great concern for many of our patients. The issue of aging and HIV infection, became an article on the New York magazine, and had a book published about it. Since then the enthusiasm for this concept has been tempered. Patients with HIV infection are at an increased risk of complications that we normally associate with the process of aging, including cardiovascular disease, osteopenia osteoporosis, diabetes etc. but that fact does not necessarily means that patients with HIV infection are aging faster than the rest of the population. For example patients with diabetes or chronic kidney disease have higher cardiovascular risk, but we do not say that patients with diabetes or CKD have accelerated aging.
There was an interesting presentation of the Veterans Administration aging cohort group (12) led by Amy Justice that emphasized this particular point. They look at the incidence of cardiovascular disease events, end stage kidney disease and non AIDS malignancies (they considered liver and lung AIDS malignancies) in patients with and without HIV infection in the VA cohort. They compared the age that these complications started and the rates between the two populations. The idea is that if patients with HIV infection are aging faster, these diseases will appear earlier in that particular population. That was not the case: these events occurred at the same age in both groups. However, the patients with HIV infection were at an increased risk of cardiovascular events, chronic kidney disease and less so of non AIDS cancers, with hazard ratios were between 1.5 and 2. That means that patients with HIV in spite of mostly having well controlled replication are still having more of these events.
I do not like the term of accelerated aging because I think it is misleading. We are all aging, yours truly too..., but I don't think there is enough data to support for the hypothesis that patients with HIV are aging faster. They do have an increased risk of some complications and it is important that we deal with these complications I think the distinction is important because aging is a complicated process that we do not quite understand, and at the present time is irreversible, and difficult to intervene. However, we do understand some of the complications associated with HIV infection and its treatment and we have many interventions to decrease the cardiovascular risk and decrease the morbidity-mortality associated with other complications.
Ongoing inflammation.
There were several presentations dealing with the issue of ongoing inflammation in patients with HIV infection with well controlled replication in the presence of antiretroviral therapy. This year was the year of the soluble markers of inflammation including IL-6, TNF alpha etc (13-14), as good predictors of bad outcomes in patients with well controlled HIV infection. Cellular markers of inflammation did not correlate very well with clinical outcomes in several cohort studies (15) and were eclipsed by markers of inflammation in macrophages (14) as clearly associated with worse outcomes and clinical manifestations of HIV.
I am reading Nate Silver book "The signal and the noise", which is entertaining, and give some insights in statistics and disparate themes as weather, poker, politics and epidemics. For the non-initiated, Nate Silver is the 5 38 blogger that predicted the results of the 2012 election for the New York Times, much more accurately than professional political analysts and polls. Paraphrasing that book, I think there is a clear signal that patients with HIV infection have increased inflammation. It has been shown in many, many studies. I think it is clear that there is ongoing inflammation and that might be the reason why patients with HIV infection, that are otherwise doing well on antiretroviral therapy still have a greater incidence of complications like on vascular events, cancers, and decrease survival. I also think there is a lot of noise in the measurements of that inflammation: in some studies some markers are elevated and in other studies other markers are elevated.... When you look at the overall evidence it seems clear to me that something is going on and that we need to understand it and deal with it, but when you look at individual studies the situation is confusing. It's going to take a while to figure out the exact reason for this problem, and many groups, as I said before, are trying to tease out the contribution of CMV replication, bacterial translocation, residual viral replication etc. etc
This persistent inflammation is probably clinically relevant. There was very interesting data presented by Steve Grinspoon's group that demonstrated that women with HIV infection, in spite of well controlled application, are at an increased risk of an unstable plaque in the coronary arteries and macrophage activation (sCD163).
Beyond pathogenesis studies, that try to understand the reasons behind this persistent inflammation, what can we do to deal with this problem? Grace McComsey presented the results of a large (147 participants) study evaluating the use of rosuvastatin in patients with HIV infection and persistent inflammation. I could not believe the study was not an oral presentation. The study showed A significant decline in the monocyte activationmarkersCD14 and proportion of CD14dimCD16+, a significant decrease in vascular inflammation marker Lp-PLA2, but little effect on markers of systemic inflammation The results were disappointing in regards to what are traditionally considered markers of cellular inflammation, but the results on markers of macrophage activation are intriguing. The key question however is to prove that this intervention is associated with improved outcomes in the long run.
I think overall it was a great meeting as usual, with a clear focus on what is going to be the main priorities over the next few years, eradication, dealing with chronic inflammation, co-infection with hepatitis C and tuberculosis.
REFERENCES
1. Deborah Persaud*, H Gay, C Ziemniak, YH Chen, M Piatak, T-W Chun, M Strain, D Richman, and K Luzuriaga. Functional HIV Cure after Very Early ART of an Infected Infant. CROI 2013. Paper #:48LB.
2. Ronald Ellis*, F Vaida, S Letendre, R Haubrich, R Heaton, A McCutchan, M Cherner, A Umlauf, N Sacktor, and D Clifford. A Randomized, Controlled Trial of a Central Nervous System-targeted ART Strategy for HIV-associated Neurocognitive Disorders. CROI 2013. Paper #:20.
3. Ignacio Perez-Valero*, A Gonzalez-Baeza, M Estebanez, N Stella-Ascariz, J Mingorance, C Bayon, M Lagarde, F Pulido, A Borobia, J Arribas, and PICASSO Study Group. Protease Inhibitor Mono-therapy Is Not Associated with a Higher Rate or a Different Pattern of Neurocognitive Impairment than Triple Drug Therapy. CROI 2013. Paper #:406
4. Priscilla Hsue*, R Scherzer, L Gilman, Y Wu, K Maka, S Mohammed, C Grunfeld, J Martin, S Deeks, and P Hunt. Effect of Maraviroc Intensification on Endothelial Function in Treated HIV Infection.CROI 2012. Paper #123
5. Hatano H, Hayes TL, Dahl V, Sinclair E, Lee TH, Hoh R, Lampiris H, Hunt PW, Palmer S, McCune JM, Martin JN, Busch MP, Shacklett BL, Deeks SG. A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis. 2011 Apr 1;203(7):960-8.
6. Hunt PW, Martin JN, Sinclair E, Epling L, Teague J, Jacobson MA, Tracy RP, Corey L, Deeks SG.Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis. 2011 May 15;203(10):1474-83
7. Paul M Ridker, M.D., Eleanor Danielson, M.I.A., Francisco A.H. Fonseca, M.D., Jacques Genest, M.D., Antonio M. Gotto, Jr., M.D., John J.P. Kastelein, M.D., Wolfgang Koenig, M.D., Peter Libby, M.D., Alberto J. Lorenzatti, M.D., Jean G. MacFadyen, B.A., Borge G. Nordestgaard, M.D., James Shepherd, M.D., James T. Willerson, M.D., and Robert J. Glynn, Sc.D. for the JUPITER Study Group. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med 2008; 359:2195-2207
8. Henning Drechsler*,, S Zhang, N Maalouf, J Cutrell, P Tebas, and R Bedimo,Impact of Statin Exposure on Mortality and Non-AIDS Complications in HIV Patients on HAART. CROI 2013. Paper #:765
9. Line Rasmussen*, G Kronborg, C Larsen, C Pedersen, J Gerstoft, and N Obe. Statin Therapy and Mortality in HIV+ Individuals: A Danish Nationwide Population-based Cohort Study.CROI 2013 Paper #:765
10. Vincenzo Spagnuolo*, L Galli, A Poli, S Salpietro, N Gianotti, P Piatti, C Vinci, E Carini, A Lazzarin,, and A Castagna. Association between Statin Use and Type-2 Diabetes Mellitus Occurrence among HIV-1+ Patients Receiving ART. CROI 2013. Paper #766
11. Kenneth Lichtenstein*, R Debes, K Wood, S Bozzette,, K Buchacz, J Brooks, and HIV Outpatient Study Investigators . Statin Use Is Associated with Incident Diabetes Mellitus among Patients in the HIV Outpatient Study. CROI 2013. Paper #767
12. Keri Althoff*, C Wyatt, C Gibert, KA Oursler, D Rimland, M Rodriguez-Barradas, K McGinnis, M Skanderson, K Gebo, A Justice, for Veterans Aging Cohort Study. HIV+ Adults Are at Greater Risk for Myocardial Infarction, Non-AIDS Cancer, and End-stage Renal Disease, but Events Occur at Similar Ages Compared to HIV- Adults. CROI 2013. Paper # 59
13. Daniel Fuster, D Cheng,, E Quinn, K Armah, R Saitz, M Freiberg, J Samet, and J Tsui. Inflammatory Cytokines and Mortality in a Cohort of HIV+ Patients with Alcohol Problems. CROI 2013. Paper #788
14. Allan Tenorio, E Zheng, R Bosch, S Deeks, B Rodriguez, S Krishnan, P Hunt, C Wilson, M Lederman, A Landay, and ACTG. Soluble Markers of Inflammation and Coagulation, but Not T Cell Activation, Predict Non-AIDS-defining Events during Suppressive ART. CROI 2013. Paper #790
15. Jason Baker,, K Huppler Hulsiek, R Bradford, R Prosser,, R Tracy, and N Key. Tissue Factor Microparticles among HIV+ Persons Are Reduced with ART and Associated with D-dimer Levels after Treatment. . CROI 2013. Paper #789
16. Kathleen Fitch*, S Abbara, T Burdo, K Williams, P Eneh, J Lo, and S Grinspoon. Non-Calcified Coronary Plaque and Macrophage Activation Markers Are Increased in HIV+ Women . CROI 2013.
17. Grace McComsey*,,, Y Jiang, S Debanne, B Clagett, J Robinson, D Labbato,,, N Storer,,, M Lederman,, and N Funderburg. Effect of Statins on Immune Activation and Inflammation in HIV+ Subjects on ART: A Randomized Placebo Controlled Trial. CROI 2013. Paper #185LB
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