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HIV Complications & It's Treatment, Opportunistic Infections, New ART Drugs, Preventing HIV Transmission: IAS. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011
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Pablo Tebas, MD
University of Pennsylvania.
This year the international AIDS conference took place in Rome. As this was an odd year (2011), the conference was smaller in size than the massive conferences on even years. It had four tracks, including basic science, clinical science, prevention and operational and implementation research. Rome is a wonderful city, although this time of the year is particularly hot. The venue of the meeting was a big concert hall in the north part of the city, probably not the best place to have this type of summit. This became particularly apparent during the poster sessions that were organized almost in a basement, separated in different areas, with very narrow hallways that reminded me more of a New York subway station during rush hour than a scientific conference. The main lecture venues were impressive concert halls with wood panels and lots of curves better suited for opera than for science, a reminder there is a reason why conference centers have evolved the way they had over the last decades... In spite of these problems, there were some terrific talks that will be remembered for years, particularly the presentation of the results of HPTN 052 in an afternoon session on Monday.
I will focus my summary on presentations about the complications of HIV and its treatment, opportunistic infections, a brief discussion of the results of new antiretroviral drug studies and of course the already highlighted results of HPTN 052.
Complications of HIV and antiretroviral treatment
There was a whole session devoted to the complications of HIV and its treatment. I thought the most interesting presentation, although I have a bias because I was an author, was Roger Bedimo's 1 using the US Veterans Case Registry database. This group evaluated the relationship between antiretroviral therapy and what is traditionally considered osteoporotic fractures (hip, spine, and wrist). The authors looked at two different periods of time: 1) the whole duration of follow-up, from 1989 to 2009, and 2) the HAART era (1996 to 2009). When considering the whole follow up there was no clear relationship between the frequency of fractures and the use of particular antiretroviral drugs after controlling for traditional risk factors for low bone mineral density like smoking, body mass index, and age. However, when the analysis was repeated in the HAART era, from 1996 to 2009, then the use tenofovir and lopinavir/ritonavir were independently associated with an increased risk of fractures. The preHAART and the HAART era are very different, and I think it's important to consider them separately. In the pre-HAART era, antiretroviral treatments were not fully suppressive (and we know that ongoing HIV replication slows bone metabolism) and patients tended to progress rapidly and died of HIV-related complications before they had time to develop fractures. Fortunately in the HAART era, thanks to fully suppressive regimens (which tend to accelerate bone metabolism), patients live longer and they can develop some of the long-term complications of HIV and its treatment. This is the first study that shows that tenofovir is associated with an increased fracture risk, something that should not surprise anybody because it has been known for several years that its use is associated with more bone loss than other antiretrovirals. The association with some boosted protease inhibitors should not come as a surprise either as there is an interaction that increases tenofovir levels when used in combination with protease inhibitors. However it is important to point out that the association between tenofovir and fractures is much smaller (RR 1.1 to 1.2) than traditional risk factors like smoking or older age, and because of that I do not think these results should affect the current use of tenofovir as first-line therapy, as the increased risk is relatively small in size, and tenofovir is a potent and well tolerated antiretroviral medication.
There were several other interesting presentations, one from Giovanni Guaraldi2 linking coronary artery calcification and bone mineral density. There has been a myriad of studies showing associations between different complications of HIV and antiretroviral treatment which many interpret as evidence that there are common pathogenic pathways between these different metabolic complications. Many scientists and clinicians think that persistent ongoing inflammation is the link responsible for the frequent association of these complications.
There were two presentations3-4 about the neurologic complications of HIV in the era of potent antiretroviral therapy that showed discordant results: a study from a single site in Italy3 suggesting, once again, that the frequency of subtle neurological abnormalities is very high among HIV-infected individuals, even when they are fully suppressed on antiretroviral therapy, although it seems to be decreasing. A second Canadian study from Ontario4 showed that the use of drugs that have good penetration in the central nervous system is not associated with better performance in these highly sophisticated neurological tests that are used to evaluate HIV associated neurocognitive disorders.
The problem of these cohort studies, as it was pointed out later by Bill Powderly, is that they lack an adequate control group of HIV uninfected individuals with a similar level of education and socioeconomic status that are tested simultaneously. I suspect that if these sophisticated tests were completed in a similar population of individuals, there would be also a high frequency of subtle neurological abnormalities. In this issue of the neurological complications of HIV in the current era there seems to be a disagreement between neurologists, who tend to think that this is a very frequent and underappreciated problem, and many clinicians who think their patients look like everybody else of the same age and sociodemographic group... I think that until a large epidemiologic study with a good control group (and not some normative standard that are generally used) this disagreement between neurologists and other clinicians will not be resolved.
In the final presentation of the session there was good news for people living with HIV5, with an update of the USA solid organ transplant study in HIV-infected individuals. Data from 125 liver and 150 kidney recipients was presented showing that HIV patients tend to do very well after a solid organ transplant and that they should not be excluded from these life-saving procedures when needed.
Inflammation and HIV disease progression
There was also a lot of discussion about the persistent high level of inflammation in some individuals that have been successfully treated with antiretroviral therapy. In a session chaired by Steve Deeks was ample discussion about the pathogenic mechanisms that drive this persistent inflammation including microbial translocation, the presence of confections like CMV, direct effect of HIV and the immune system. There is a need to evaluate simple clinical interventions like the use of anti-inflammatories or statins to see if decreasing this persistent inflammation with the use of these or other therapeutic agents have clinical benefits in the long run.
Opportunistic infections
The international AIDS conference usually reserves a large section of the presentations to internationally relevant research. There were several presentations about IRIS, with a particular focus on paradoxical tuberculosis IRIS, its predictors and its relevance in early mortality in patients with HIV infection. In the CAMELIA trial (a trial conducted in Cambodia comparing early treatment with antiretroviral therapy in patients with tuberculosis versus delayed treatment)6, 26% of the participants developed TB IRIS. The most frequent symptoms were enlarged lymph nodes, fever and abdominal pain. Most of the symptoms appear within a few days of the initiation of antiretroviral therapy. As expected IRIS occurred more frequently in individuals that started therapy earlier with very low CD4 cell counts and extrapulmonary TB. IRIS tended to respond to standard treatment, including in many cases steroids, and it was a very uncommon cause of death. In the CAPRISA trial7 (a similar trial of early vs delayed antiretroviral therapy conducted in South Africa) the frequency of of IRIS were a little bit lower (the patients started therapy with higher CD4 cell counts in this study), and in this case the most frequent symptom was worsening respiratory status. Although the figures of IRIS after starting therapy, particularly in the developing world seem high, it is important to remember that there is no reason to delay therapy because of fear of this complication particularly in individuals with advanced disease and very low CD4 counts, as early therapy has been associated with an improvement in mortality greater than 20%. There was a very interesting presentation from Dr. Livio Azzoni8 that suggested that activation of the CREB pathway is critical in the pathogenesis of TB associated IRIS. As he pointed out larger studies with adequate controls will be needed to completely understand the pathogenesis of this very frequent complication.
In the late breaker abstract session there was a very interesting presentation9 evaluating the use of a urine test to detect glucuronoxylomannan (GXM) in individuals with a concurrent or a recent diagnosis of cryptococcal disease. This is an important study because the diagnosis of cryptococcal meningitis in the developing world has been plagued with poor diagnostics and the need to perform a spinal tap. The test was positive in 61 of the 62 patients, showing an excellent sensitivity. It will require further validation, but if these encouraging results are confirmed in a larger population, it would be a significant improvement in the diagnosis of this life threatening infection.
New antiretrovirlas
Although there were not very many presentations about new antiretrovirals I would like to highlight the following:
· A larger study demonstrating that elvitegravir is equivalent to raltegravir in the treatment of patients with virological failure10. Although the conclusions of this trial have been announced before the meeting, this is an important study as it will almost certainly lead to the approval of elvitegravir in the US. This was also the first large phase 3 equivalence trial for the treatment of individuals with antiretroviral resistance. In the past we were accustomed to superiority trials for this particular indication, but because the development of multiple new drugs, and the high rate of success when at least three completely active drugs are used, the design of those trials had to be changed to equivalence trials, which are much larger in size (and unfortunately more expensive).
· A phase 2 study (dose finding) of lersivirine11, a new NNRTI which compared it at doses of 500 and 750 mg daily to standard efavirenz in combination in both cases with TDF/FTC. The drug seemed equivalent (maybe a little less potent than efavirenz: 86% vs 79% undetectable viral loads at week 48). Side effects were frequent with this new drug, particularly nausea and headaches, which I think may complicate its development (from Jules: ViiV told me the nausea was almost all grade 1 or, no grade 3 or 4)
· Glaxo presented in the results of the SPRING-1 trial12, another dose finding study, of dolutegravir (3 different doses 10, 25, or 50 mg, merged into the final selected dose of 50mg a day) compared to efavirenz (with TDF/FTC). This new drug was very well tolerated and had an impressive, almost 90% virological success rate, at the end of the follow up. There were slight increases in creatinine in the dolutegravir arms that were not associated with decreases in creatinine clearance. The drug seems to affect the tubular secretion of creatinine (in a similar way than TMP-SMZ). Phase 3 trials are currently ongoing for this very interesting potent, once a day compound.
· A study comparing a traditional triple drug regimen that included tenofovir, FTC and atazanavir/ritonavir vs a "nucleoside sparing" regimen of maraviroc (150 mg daily) and atazanavir ritonavir13. The study showed again what has been seen in other "nucleoside sparing studies": a slightly decreased efficacy when using a non conventional regimen. These results are an important reminder that these types of experimental regimens should not be used outside of a well-controlled clinical trial, as they may be associated with a lack of efficacy.
Treatment as prevention
The several presentations associated with study HPTN 05214, were the most important presentations of the meeting, and probably some of the most important presentations of the last few years. During the session I felt that I was part of a historical moment, which will be remembered in the years to come. If you want to commit to memory just one study from this meeting, this is the one.
HPTN 052 evaluated the effect of antiretroviral treatment on HIV transmission in sero-discordant couples. The idea is that by treating the HIV-positive member of the couple it is possible to prevent the transmission of HIV to the negative individual. There have been several studies that suggested that this was the case, but this study proved it beyond any doubt. In this study, 1730 couples in which one of the members was HIV-positive and had relatively high CD4 cell count (350 to 550 cells/mm3) were randomized to receive immediate antiretroviral therapy or delay it until the CD4 cell count was 250 or the individual developed an AIDS defining illness (this was the standard of care in most of the developing world at the time the study was initiated). All participants were educated about HIV and given condoms (male and female) to prevent the transmission of HIV. The use of antiretroviral therapy reduced the transmission of HIV by 96%. The results were so impressive that the DSMB (Data and safety monitoring Board) that evaluated the study decided to stop it and advised that every individual should receive antiretroviral therapy to prevent the transmission to others. The early initiation of antiretroviral therapy not only reduced transmission to the seronegative individuals in the couple, it also reduced the frequency of AIDS-related events, deaths, pulmonary tuberculosis and serious bacterial infections in the positive individuals, suggesting that the early initiation of antiretroviral therapy has additional beneficial effects even when it is started relatively early (as it was in this study).
The study has profound implications because it validates the TEST and TREAT approach that has been suggested as a potential way to decrease the number of HIV transmissions. If you think about it, any HIV transmission, always occur between a discordant couple, in which the positive individual infects the negative. Most of the times the positive individual does not know his or her status and it is not receiving treatment, and this is when transmission occurs. If we could identify all HIV positive individuals and give them treatment, we could potentially reduce the transmission of HIV by at least 96%, and finally make a dent in this ongoing epidemic. I anticipate that because of the results of this study there will be a push for universal testing for HIV and linkage to care and treatment.
There were two additional presentations during this memorable session: they discussed the results of two of the preexposure prophylaxis trials, one being conducted in Botswana, the TDF2 study and the partners PrEP study 15-16. Both studies showed remarkable similar conclusions tenofovir alone (Botswana study and one arm of the partners PrEP study) or tenofovir + FTC, is effective in preventing the acquisition of HIV infection by 62 to 73%. a very impressive result by all means. As Toni Fauci said: if we had a vaccine this effective we would approve it. These numbers are two times as effective as the microbicide trial17 (CAPRISA 004) that was presented last year in Vienna and published in Science. The results of these studies also have immediate implications for the ongoing preexposure prophylaxis studies that include a placebo arm: should we close those studies (or at least the placebo arms) now that we know that pre exposure prophylaxis is effective, or do we continue them to completion?
The session highlighted the two, not necessarily mutually exclusive approaches, to reduce the incidence of HIV infection in the world until we have an effective protective vaccine. One approach is to try to identify all HIV positive individuals, bring them to care, initiate antiretroviral therapy and prevent the transmission to others (HPTN 052 approach). The second approach is to give preexposure prophylaxis to high-risk individuals (PREP approach), thus decreasing the transmission of HIV infection in those individuals that receive prophylaxis. Clinicians like me like the "test and treat" approach, as we are giving therapy to infected individuals that need it in any case, which has the additional benefit of preventing the transmission to others. The preexposure prophylaxis approach is more complex, it is very expensive as it is difficult to identify individuals that would benefit the most from this intervention. In the United States there is the lingering question of who is going to pay for this intervention?; most of the high risk groups for acquisition of HIV are uninsured or poorly insured. I do not see the creation of an entitlement similar to the Ryan White Title Act to provide access to PREP to individuals at risk. It is simply unfathomable that this type of discussion will take place in the current US Congress where the Tea Party reigns. Unless the cost of tenofovir is reduced dramatically I simply cannot imagine a large-scale implementation of this approach in the current economic environment. I do not see it either in the developing world, where a significant proportion of HIV positive individuals that need antiretroviral therapy do not have access to it (a problem that is starting to occur in some States in the South, like North Carolina and Florida). This is a sad reminder that there are two ways to close the gap between the rich and the poor countries: it is possible to improve the care in the poor countries, but it is also possible to worsen the care in the developed world. Let's hope that our politicians do not opt for the second option.
References
1. R. Bedimo,, S. Zhang, H. Drechsler,, P. Tebas, N. Maalouf. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# MOAB0101
2. A. Bellasi, S. Zona, G. Orlando, F. Carli, S. Cocchi, G. Ligabue, V. Rochira, P. Bagni, P. Raggi, G. Guaraldi. Coronary artery calcification is associated with femoral but not with lumbar spine mineral density. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# MOAB0102
3. P. Balestra, V. Tozzi, M. Zaccarelli, R. Libertone, G. Cataldo, G. Liuzzi, S. Menichetti, M. Giulianelli, P. Narciso, A. Antinori I.N.M.I. L Spallanzani. Prevalence and risk factors for HIV associated neurocognitive disorders (HAND), 1996 to 2010: results from an observational cohort. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# MOAB0103
4. S.B. Rourke,,, A. Carvalhal, A.R. Zipursky,, T. Bekele, J. McCombe,, A. Rachlis,, E. Collins, M.J. Gill, J. Raboud,, A. Burchell,Examining the impact of CNS penetration effectiveness of combination antiretroviral treatment (cART) on neuropsychological outcomes in persons living with HIV: findings from the Ontario HIV Treatment Network (OHTN) cohort study. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# MOAB0104
5. G. Beatty, B. Barin, L. Fox, J. Odim, S. Huprikar, M. Wong, J. Diego, E. Blumberg, D. Simon, J. Light, M. Yin, C. Davis, D. Jayaweera, D. Hardy, M. Ragni, L. Johnson, A. Subramanian, V. Stosor, K. Brayman, K. Pursell, R. Zhang, G.M. Lyon, A. Taege, J. Feinberg, B. Weikert, P. Stock, M. Roland. HIV-related predictors and outcomes in 275 liver and/or kidney transplant recipients. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# MOAB0105
6. D. Laureillard,, O. Marcy, Y. Madec, S. Chan,, L. Borand, N. Prak, C. Kim,, K.K. Lak,, C. Hak, B. Dim,,, E. Nerrienet, T. Sok, A.E. Goldfeld,, F.X. Blanc. Incidence and risk factors of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome in HIV-infected adults enrolled in the CAMELIA clinical trial (ANRS 1295/12160 - CIPRA KH001/10425). 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# WEAX0104
7. K. Naidoo, N. JIthoo, N. Yende, N. Padayatchi, K. Naidoo, S. Abdool Karim. ,Immune reconstitution inflammatory syndrome following antiretroviral therapy initiation during tuberculosis treatment. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract#WEAX0105
8. N. Dawany, A. Kossenkov, C. Chang, F. Conradie, I. Sanne, L.J. Montaner, L. Showe, L. Azzoni. Activation of the CREB-dependent pathway distinguishes M.tuberculosis-mediated immune reconstitution syndrome (IRIS) from chronic HIV and HIV-MTB co-infection. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# WEAX0103
9. J.N. Jarvis,, A. Percival, S. Bauman, G. Meintjes,,, G.N. Williams, N. Longley,,, T. Harrison, T. Kozel. Evaluation of a novel point of care cryptococcal antigen (CRAG) test on serum, plasma and urine from patients with HIV-associated cryptococcal meningitis. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# WELBB04
10. B.-M. Molina, A. LaMarca, J. Andrade Villanueva, B. Clotet, N. Clumeck, Y.-P. Liu, L. Zhong, A. Cheng, J. Szwarcberg, S.L. Chuck, for the Study 145 Group. Elvitegravir once-daily is non inferior to raltegravir twice-daily in treatment experienced patients: 48 week results from a phase 3 multicenter, randomized, double blind study.
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# WELBB05.
11. P. Vernazza, C. Wang, A. Pozniak, E. Weil, P. Pulik, D. Cooper, R. Kaplan, A. Lazzarin, H. Valdez, J. Goodrich, C. Craig, J. Mori, M. Tawadrous. Efficacy and safety of lersivirine (UK-453,061) vs. efavirenz in antiretroviral treatment-naïve HIV-1-infected patients: week 48 primary analysis results from an ongoing, multicentre, randomised, double-blind, phase IIb trial (study A5271015). 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# TUAB0101
12. J. Van Lunzen, F. Maggiolo, B. Phung, O. Tsybakova, B. Young,, J. Gatell, S. Almond, M. St. Clair, C. Brothers, S. Min Rapid, robust and sustained antiviral response with once-daily (QD) dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral-naïve adults: 48 week results from SPRING-1 (ING112276). 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# TUAB0102
13. S. Portsmouth, C. Craig, A. Mills, D. Mildvan, D. Podzamczer, G. Fatkenheuer, M. Leal, H. Valdez, S.R. Valluri, J. Heera. 48-week results of a dual-therapy regimen of once-daily maraviroc (MVC) 150 mg in combination with ritonavir-boosted atazanavir (ATV/r) compared to emtricitabine/tenofovir (FTC/TDF) + ATV/r in treatment-naïve (TN) patients infected with CCR5-tropic H. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# TUAB0103
14. M. Cohen, Y. Chen, M. McCauley, et al. Antiretroviral treatment to prevent the sexual transmission of HIV-1: results from the HPTN 052 multinational randomized controlled trial. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract# MOAX0102
15. M.C. Thigpen, P.M. Kebaabetswe, D.K. Smith et al. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract#WELBC01
16. Jared Baeten et al. Antiretroviral Pre-Exposure Prophylaxis for HIV-1 prevention among heterosexual African men and women: the Partners PrEP Study. . 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome 17-20 July, 2011. Abstract#MOAX0106
17. Quarraisha Abdool Karim,1,2* Salim S. Abdool Karim,1,2,3* Janet A. Frohlich,1 Anneke C. Grobler,1
Cheryl Baxter,1 Leila E. Mansoor,1 Ayesha B. M. Kharsany,1 Sengeziwe Sibeko,1 Koleka P. Mlisana,1
Zaheen Omar,1 Tanuja N. Gengiah,1 SilviaMaarschalk,1 Natasha Arulappan,1 MukelisiweMlotshwa,1
Lynn Morris,4 Douglas Taylor,5 on behalf of the CAPRISA 004 Trial Group. Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women. Science 2010; Sep 3;329(5996):1168-74. Epub 2010 Jul 19.
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