New Insights on HIV/HAART Complications & Coinfections: Highlights From the XVII International AIDS Conference

Table of Contents

• Introduction

• Inflammation, HIV and HIV Therapy
  
• Reducing Visceral Adipose Tissue
  

• Pregabalin for Peripheral Neuropathy: Does It Really Work?
  

• Noteworthy Research on Viral Hepatitis
  

• Conclusion
  

• References

Note: This CME/CE activity expired on August 13, 2009. For a list of currently available activities, click here.

Introduction

Greetings from Mexico City. I'm here to talk to you about some of the sessions at the XVII International AIDS Conference [AIDS 2008] that dealt with complications of HIV and HAART [highly active antiretroviral therapy]. I'll also touch on viral hepatitis, because there were some interesting posters at the conference regarding viral hepatitis and HIV.

As far as complications of HIV therapies (and HIV itself) go, we are entering a new era. This is an era in which we have begun to think a little bit more about inflammation and coagulation than we ever thought we would need to. I think this marks what often happens in HIV medicine: We're confident that we're HIV therapists, that we can use infectious disease principles. Then, before you know it, we're starting to order DEXA [dual energy X-ray absorptiometry] scans. We're starting to interpret lipid values. We're starting to stretch out of our comfort zone, embracing other aspects of medicine that we never imagined we would have to encounter.

This is what's happening now in HIV medicine. And at every conference we are going to be at for the foreseeable future, we will hear the words "cytokines," "thrombogenesis," "fibrinogen" and "interleukins" increasingly mentioned, because this is not going away. Thus we must try to understand the complications we're seeing emerge in patients on HIV therapy, and what happens to people with HIV who are not treated appropriately or adequately.

Inflammation, HIV and HIV Therapy

What we're going to concentrate on first in this review is how thoughts are evolving with regards to inflammation and its role in some of the adverse events that occur in people with HIV, as well as what data we saw at AIDS 2008 to help advance that line of thinking.

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I think the best presentation to sum this up and put this all in perspective was done by Judith Currier, who is a master at doing this kind of review. She completely understands the data and is able to synthesize a message for the rest of us that is easy to digest. If there's one session that I would download from the conference Web site, it would be her review of the role of inflammation, cardiovascular disease and other metabolic effects of HIV and its therapies.¹

Her summary slide sums up the state of the art today and demonstrates that there is clearly a link between HIV replication and inflammation. This is largely mediated through immune activation: The immune system reacts to the virus. Remember, high levels of HIV are present in patients who are not treated. Inflammation ensues, and when there's inflammation, you have recruitment of macrophages; you have cytokine release, a so-called "inflammatory storm" that can lead to the secretion of other chemicals that can propagate inflammation.

We also know that when inflammation occurs, there are changes in a patient's endothelium; endothelial function is impacted by these inflammatory cytokines. Through endothelial dysfunction, we might see atherogenesis develop. Inflammation can also lead to insulin resistance, further promoting atherogenesis.

What about HIV therapies? We know HIV therapies themselves can lead to insulin resistance,² and we also know that they can affect lipids.³ Atherogenic lipids can increase in concentration with the use of some antiretrovirals, including most of the older antiretrovirals.

Finally, HIV itself can alter lipids. In the era before HAART, HIV-infected people experienced very high triglyceride levels⁴ and low HDL [high-density lipoprotein] cholesterol;⁵ those are the hallmark dyslipidemias that we see with HIV. Those altered lipids can also promote coronary artery disease and other atherosclerotic conditions.

Diabetes, genetics and lifestyle -- e.g., smoking and hypertension -- are factors that can further synergize with the effects I've just discussed, leading to blockages of major arteries. What we, as HIV health care providers, have to start understanding better are the connections between all of these assorted causes of inflammation.

We know that when patients are on HIV therapy, replication of HIV is suppressed. That should theoretically shut down immune activation, and shut down some inflammation with it. We saw from the SMART study that this does seem to happen: People who discontinued their therapy had more inflammation than people who continued their HIV medications.⁶ There is also evidence that people who restart their HIV medications after a treatment interruption see a diminution of immune activation and inflammation, albeit not to the same level as it was before they stopped their HIV medications.⁷

We also know that starting HIV medications leads to endothelial improvements; that the dysfunction in endothelial cells and endothelial function that we see in patients with unchecked viremia seems to be reversed by starting HIV therapy.⁸ Yet, despite all of this, there may be some role for HIV therapy in increasing inflammation.

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Can HIV therapy lead to inflammation through a mechanism that we have not measured yet? That is a question that was discussed, but also sort of skirted on, during this conference. There weren't a lot of data attempting to pinpoint the effects of HIV therapy on inflammatory markers.

There were data from the HEAT study, presented by Kimberly Smith, which indicated that there weren't any differences in inflammatory markers between those on tenofovir [TDF, Viread] and those on abacavir [ABC, Ziagen].⁹

However, we have seen that patients overall do better with regards to inflammatory markers while on therapy. Thus, there may be some individual differences between therapies that we're not measuring, but that we may be able to detect using other markers of inflammation. I think that bears further study.

Several studies were presented here that looked at unique markers of inflammation, including urinary markers.¹⁰

There were also some comparisons between people on HIV therapy, those who were not on HIV therapy and people who were not HIV infected.¹¹ Preliminary data; nothing conclusive here. But these are the first steps that will lead us down the road to a better understanding of what's going on vis-à-vis inflammation in our patients.

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At conferences to come, I think we'll get closer and closer to understanding exactly what's going on as far as inflammation, HIV and HIV therapy are concerned. One point that Dr. Currier made in her presentation that I feel is important is that the type of inflammation -- and the type of damage generally -- that we see with uncontrolled HIV dwarfs the effects we're seeing with HIV therapy. The benefits of HIV therapy clearly outstrip any concerns that we have discussed in this review.

The problem for a clinician dealing with all of these data about inflammation is what to do about it. Unfortunately, we really don't have that kind of information right now. At the 15th Conference on Retroviruses and Opportunistic Infections in February, there was one small study in which individuals with HIV were given pentoxifylline [Pentoxil, Trental], which is known to be an anti-inflammatory; there were some changes seen in inflammatory cytokines.¹² But we really don't have anything definitive that we're "supposed" to do now regarding inflammation.

In my opinion, the best anti-inflammatory we have at the moment is HIV therapy. I think it's premature to start recommending our patients take aspirin or other anti-inflammatories. Not all anti-inflammatories are created equal: Not all of them do exactly what we would want them to do, and most have some toxicity associated with them.

At this point, the inflammation issue is an evolving story. We're still trying to create a unifying understanding of what we're seeing clinically, both in terms of what HIV therapy does, and in terms of what HIV itself does. I genuinely think we're at the cusp of a greater understanding -- a common denominator -- for some of the complications we're seeing in our HIV-infected patients, and of a realization that these complications are mediated through some of these inflammatory conditions. Part of that, of course, is also due to the thrombosis cascade. We know that inflammation and thrombosis are related,¹³ and that could really help explain some of the problems we're seeing, especially when it comes to cardiovascular disease, and perhaps kidney disease, liver disease and even neurologic aspects of HIV.

So I think, again, we're at the beginning of an understanding. It's premature to recommend that we do anything to intervene therapeutically at this point.

Reducing Visceral Adipose Tissue

Moving to another area within the realm of complications, there were two interesting studies on visceral adipose tissue that I think will be very meaningful for most of us and our patients.

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The first study, by Graeme Moyle, looked at switching HIV therapy for individuals who had increased abdominal girth (visceral adipose tissue).¹⁴ The idea behind this study was to determine whether we could take patients with excess abdominal girth and switch them from their current, ritonavir [RTV, Norvir]-boosted protease inhibitor [PI] to ritonavir-boosted atazanavir [ATV, Reyataz].

The motivation behind this study, which was conducted in London, was that ritonavir-boosted atazanavir probably leads to less insulin resistance than other boosted PIs.¹⁵ Also, there is a perception that atazanavir is more metabolically neutral than other PIs that are boosted with ritonavir.¹⁶ (Whether that's true is not very clear, but there is that perception.)

This study involved taking a large group of individuals who were on other PIs, largely lopinavir/ritonavir [LPV/r, Kaletra] -- that was about 70% of the cohort -- and switching them to ritonavir-boosted atazanavir.¹⁴

The bottom line was, there was no change at all in visceral adipose tissue among patients who switched, compared to those who continued on their original boosted PI. Visceral adipose tissue did not change, when measured by CT [computed tomography] scan; subcutaneous fat did not change. Lipids changed, as one would expect: When switching from the other PIs to atazanavir, there were some benefits seen with regards to triglyceride levels and non-HDL cholesterol. There were no surprises here.

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What this means is that we shouldn't just assume that, because atazanavir seems to be a little bit better than other PIs as far as lipids are concerned,¹⁶ we're going to see any differences in abdominal fat among patients who switch to it.

During the question-and-answer period, Dr. Moyle was asked why the study was conducted. He indicated that there was a perception that there is a link between insulin resistance and visceral adiposity that needed to be explored. Perhaps, however, that link is associated more with older PIs, such as indinavir [IDV, Crixivan]; we have clearly seen that indinavir can cause insulin resistance¹⁷ and visceral adiposity.¹⁸

So do PIs really cause abdominal fat increases? I think there was at least some consensus among those in the room that perhaps that assumption should be rethought. Recent data certainly bear out that this adverse event does not seem to be specific to this class of drugs.¹⁹

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A second study, by Julian Falutz, looking at visceral adiposity examined the use of the growth hormone releasing factor known as tesamorelin.²⁰ This is a very interesting compound that's a little bit higher up the chain of events leading to growth hormone secretion. Growth hormone deficiency has been associated with visceral adiposity and buffalo hump;²¹ we know growth hormone can help reverse buffalo hump, although it is difficult to administer and has some toxicity.²²

Previous study results found that growth hormone releasing factor was effective at reducing visceral adiposity to a significant degree.²³ Visceral adiposity (measured by CT scan), as well as abdominal girth (measured across the belly), improved dramatically in patients who received the drug, and was clearly noticed by the individuals who received the active compound.

This study looked to confirm those results, probably for registrational purposes. A total of 404 individuals were randomized 2-to-1 to receive either growth hormone releasing factor at 2 mg subcutaneously or placebo.²⁰ As in the previous study, trial participants experienced early improvements. The results were limited to just the first 26 weeks, but already at least a 0.5-kg reduction in visceral adipose tissue was seen among those who received the active drug versus placebo. The placebo group saw almost no change at all in adipose tissue volume in the abdomen.

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There were minimal changes seen in subcutaneous fat, either in the abdomen or in the limbs, and there were no changes in lipids. Insulin-like growth factor did increase in those who received the growth hormone releasing factor, but it seemed to increase within the physiologic range, and did not seem too concerning given that insulin and glucose levels didn't seem to change. This is another feather in the cap of growth hormone releasing factor. I think the drug is well on its way to getting U.S. Food and Drug Administration approval for the treatment of visceral adiposity associated with HIV and its therapies. One can only hope that the drug will be priced in a way that makes it accessible for the many people who could benefit from it.

Pregabalin for Peripheral Neuropathy: Does It Really Work?

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Lastly, I'll touch upon two issues that are a nagging concern in our clinics: One is peripheral neuropathy and the other is viral hepatitis.

Any clinician who sees patients with HIV knows that peripheral neuropathy remains a major clinical challenge. Estimates show that between one-third and one-half of individuals with HIV experience painful peripheral neuropathy at some point during the duration of their disease,²⁴ and there have been very limited modalities for treating it. Oftentimes we rely upon therapies that have not been well studied or on pain relievers, such as narcotics.

Pregabalin [Lyrica] is an anticonvulsant that has been increasingly used in our clinics for the treatment of peripheral neuropathy, especially for those patients who do not benefit from gabapentin [Gabarone, Neurontin] or other therapies that we use more commonly.

Pregabalin has been found to be effective in the treatment of diabetic peripheral neuropathy, as well as postherpetic neuralgia,²⁵ but it has never been studied in the context of HIV infection until now.

This was a study that was launched in 302 patients who had neurologist-confirmed painful peripheral neuropathy.²⁶ Patients were randomized to pregabalin at a dose of 150 mg per day, escalating to 600 mg per day, versus placebo. The duration of time that the drug was administered was 14 weeks.

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The bottom line from this study was that those who received pregabalin experienced a significant, positive change in their pain scores. However, remarkably, so did individuals who received the placebo. In fact, the placebo effect in this study was quite profound; it almost matched that of the active drug.

Importantly, the placebo effect seen here -- over 30% response -- was much more than what has been seen in most placebo-controlled studies of peripheral neuropathy. It is not clear why HIV-infected patients might have a greater placebo effect, but I think it calls into question whether there's any benefit of pregabalin over placebo in a clinical context. Certainly, it was not a very encouraging result for those of us who have relied upon pregabalin to treat peripheral neuropathy.

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A silver lining, however, might be that in one of the instruments used to measure global improvement in patient-reported disease, there was a significant improvement among those who received pregabalin compared to placebo. This was a measure of how well patients feel they are doing when compared to when they initiated the study. It's much more universal than the pain assessment that was used as the primary endpoint.

Pregabalin, for what it's worth, was well tolerated, although it did cause more somnolence. But it also caused a little bit more euphoria. I don't know if that's a good thing or a bad thing, but people seem to feel pretty well on it, although they were a little bit sleepier.

Overall, I am not sure what to make of this. I think people who like to use pregabalin will be convinced that it is a helpful agent and will be impressed by the response rates seen in the study, rather than dissuaded from its use by the placebo effect. Hopefully there is nobody out there tempted to use placebo, but the placebo effect in this study certainly bears some scrutiny. Perhaps other studies will be conducted that will have a more specific endpoint that can help us tease out differences between a placebo group and an active treatment group.

Noteworthy Research on Viral Hepatitis

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Lastly, I'm going to touch upon viral hepatitis. There wasn't much meaningful data presented on this subject at AIDS 2008. However, there were two presentations that I thought were interesting.

One was a presentation on psychological morbidity among people who are candidates for hepatitis C [HCV] therapy.²⁷ This was a study conducted in New York. The idea was to understand the psychiatric comorbidity at the initiation of HCV therapy in people who were HCV monoinfected compared to patients who were coinfected with both HIV and HCV.

What the researchers found, interestingly enough, was that when you look at patients who are about to commence HCV therapy and administer validated measures of depression and other psychological conditions, people who were HIV infected actually had lower levels of psychiatric comorbidity compared to people who were HCV monoinfected. This suggests that perhaps we're discriminating somewhat in recommending therapy for individuals who are coinfected with HIV and HCV, compared to those who are only HCV infected. There may be additional coinfected people who we feel are not good candidates for therapy when, in actuality, if they were HCV-monoinfected patients, we would find therapy acceptable.

This is a provocative study. It leads us to question which patients are eligible for HCV therapy and which are not. Perhaps we should raise the bar a little bit when looking at the psychiatric and psychological comorbidity of our patients with HIV infection.

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Lastly, in the realm of hepatitis B and C, there was an interesting report from Russia in which researchers looked at HIV-infected pregnant women who were coinfected with HCV and compared them to HIV-infected pregnant women who were not coinfected with HCV.²⁸ The researchers examined the outcomes following the birth of their children, and examined transmission of both viruses.

Remarkably, what they found was that HCV coinfection was associated with increasing a woman's risk of transmitting HIV as well as HCV to her infant. This was a large study of more than 1,800 women, so I think that we have to pay attention to this. Certainly, for women who are HIV/HCV coinfected and who are pregnant, we should concentrate on the HIV, but we should not neglect to think hard about the HCV as well.

In fact, there have been previous studies that have indicated that HIV/HCV coinfection may be an indication for cesarean section in order to reduce the risk of perinatal transmission of HCV.^29,30 Perhaps it is also important to use this procedure among HIV/HCV-coinfected women to reduce transmission of HIV. Hopefully, there will be more data soon that will help us understand the role of HCV and perinatal transmission of HIV.

Conclusion

This was a big conference. It was very diverse and diffuse. That said, there were not a lot of new, headline-worthy data presented here. I think the inflammation story is one that's evolving; we saw it progress a little down its path at this conference, with a whole session dedicated to the issue.³¹

We saw some tidbit studies that may help us understand a little bit more about the impact of what we do in the clinic, especially when it comes to the use of pregabalin for peripheral neuropathy.

And finally, we're beginning to understand that HCV therapy may deserve to be seen as a more attractive option for some of the patients for whom we previously thought therapy was a really bad idea. We should instead think hard about using these therapies, especially given the high morbidity and mortality we're seeing in our clinics due to viral hepatitis.

This transcript has been lightly edited for clarity.

References

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   View slides: Download PowerPoint
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   View poster: Download PDF
10. Boger M, Milne G, Morrow J, et al. A pilot study of urinary markers of endothelial function and oxidant stress for the prediction of cardiovascular disease (CVD) risk with antiretroviral therapy (ART). In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City, Mexico. Abstract WEAB0105.
    View slides: Download PowerPoint
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    View poster: Download PDF
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    View slides: Download PowerPoint
27. Weiss J, Brau N, Dieterich D, Fishbein D. Higher prevalence of psychiatric comorbidity at initiation of hepatitis C therapy in HCV-monoinfected compared to HIV/HCV-coinfected patients. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City, Mexico. Abstract WEPE0175.
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