Strategic Drug Interruptions Will Holidays from Drug Cocktails Become a Reality?

A New Tool For New Treatment Complications

Pipeline Mania: New and Promising Anti-HIV Drugs in Development

The latest FAT Facts & Abnormal Changes in Body Composition

HIV Positive Women Have Higher Risks for Developing AIDS

HIV Suppression vs. HIV Cure

Cigarette Smoking

Highlights from the 3rd International Conference on Nutrition and HIV Infection Cannes, France: April 22-25, 1999

Briefs from the 6th Retrovirus Conference Held in Chicago

Strategic Drug Interruptions Will Holidays from Drug Cocktails Become a Reality?
By Matthew Sirinek MD

Treatment of HIV-positive patients with highly active antiretroviral therapy (HAART, antiviral drug cocktails) has been shown to reduce HIV viral loads to below the level of detection in the blood of many patients. This has allowed for a significant degree of immune restoration that allows HIV + patients to have productive and healthy lives. It has become clear, however, that HAART is unlikely to ever completely eradicate the virus from all reservoirs in the body.

Given that eradication of the HIV virus from the body appears unrealistic, attention has now focused on how to deal with HIV infection in the long term. One approach that has received a great deal of attention lately is structured treatment interruptions (STI). This approach suggests that individuals can intermittently stop their HAART for a given amount of time sometimes as part of a given research protocol. Patients then alternate between being on and off therapy in structured intervals. Sometimes during the course of treatment, a physician may decide that treatment interruption is warranted. Certain guidelines should be followed and agreed upon by the patient. Close monitoring is necessary to ensure that the risks are minimized.

From the surface there are several justifications for STI. Firstly, it provides patients with a reprieve from taking these demanding and sometimes toxic medications. Perhaps the risks of developing lipodystrophy and metabolic abnormalities may be minimized due to less drug exposure. Also, patients may be less likely to develop treatment fatigue or long-term side effects that can lead to non-compliance and viral resistance. Treatment interruptions can also result in large cost savings due to the expensive antiviral drug therapy being interrupted. Finally, while off HAART, rebound of HIV viral load to detectable levels is almost always observed. This viral rebound is definitely concerning, but it is theorized that allowing the virus to rebound temporarily may actually help to boost the immune response to HIV in the same way a booster immunization would. When the HIV viral load is undetectable in the blood there may not be enough virus circulating for our immune systems to mount an effective response. Thus, stopping therapy allows the virus to rebound in the bloodstream and the immune system, exposed to HIV may develop a stronger HIV-specific response to the virus. This might allow better control of viral replication in the future. However, one needs to understand that there are risks with treatment interruptions coupled with the knowledge that antiviral therapy on its own has certainly been successful at boosting patientsГ• immune systems by depressing the virus. Indeed it is antiviral treatment that has saved many lives.

The immune response to HIV is still not completely understood. Recent studies have indicated that HIV-specific immunity diminishes with time in patients on HAART. Thus it appears that while HAART diminishes the amount of virus in the blood thereby helping the immune system to recover, the viral load may remain too low for the immune system to recognize and respond to it while on HAART. The immune system appears to be inhibited from responding to HIV when the drugs inhibit the virus to undetectable levels in the blood, and may not participate as much in helping to control the virus in concert with the drugs.

While STIs sound intriguing and are worthy of further studies, there are many unanswered questions that need to be answered before considering this option. First, the time intervals for being on and off HAART have not been adequately determined. There are many studies trying to determine this currently. Secondly, any time a patient is taken off therapy there is a risk of developing resistance to the regimen as the viral load increases. Thirdly, not every patient is ideal for STIs. Patients with low T cell counts may not be suitable for treatment interruption. Their counts may be too low to adequately develop a good HIV-specific immune response off therapy resulting in a drastic decline in T cell counts when taken off their medications. This decline may expose them to unneeded risks for developing opportunistic complications. A recently reported study documented furthering AIDS events in some individuals during a treatment interruption study.

While STIs remain a very intriguing and enticing way to treat many HIV patients in the future, it is important to recognize that more studies are needed to determine the safety and efficacy of this treatment option. Not all patients will be suitable for this treatment option and many questions need to be answered before we consider using STIs in every day practice.

The notion that STIs may be beneficial came from the work of Drs. Lori and Walker and involved the famous "Berlin patient." This patient was placed on HAART during primary infection with HIV. He had two treatment interruptions, the second of which was not accompanied by a viral rebound. He elected to stay off therapy after that and no virus was detected in his blood 18 months later. He was found to have strong HIV-specific CD4 and CD8 cell responses. It is not clear if either the early intervention with HAART or the subsequent drug interruptions were responsible for the patientГ•s ability to control his virus below the level of detection. He may have been naturally destined to be a long-term non-progressor. Nonetheless, this patientГ•s success has led to trials of STI in an attempt to boost the HIV-specific immune response in patients on HAART.

Early reports suggested that STIs could have deleterious effects on the immune system. One study involved some chronically infected patients on HAART who had achieved undetectable viral loads. All of these patients stopped HAART and their viral loads all rose to above the pre-treatment levels within 2 weeks. This rebound of virus was also associated with a decrease in T cell counts.

A New Tool For New Treatment Complications
Daniel S. Berger MD

The new millennium has brought new complexities of treatment and created more challenges to HIV experts treating individual patients. More of our patients have been living longer but changes in their treatment cocktails are often needed. At times treatment must be altered because of intolerable side effects, but at times drug resistance has developed.

The term resistance refers to reduced ability for the antiviral medications to suppress HIV replication, which ultimately leads to rising viral load, sometimes despite a consistency in taking oneГ•s medications. To explain the viral ability to replicate over and beyond the barricade of antiviral drug defense is to explain mutant HIV strains. The viral ability to replicate is a result of its ability to mutate or change its genetic make-up, which then eludes and evades the antiviral effect of specific drugs. In other words these mutational strains of HIV are resistant to the effects of antiviral drugs that the individual patient is taking. How high a viral load reaches before we describe a patient to have resistance is not clearly defined and is often subject to a physiciansГ• opinion.

Physicians who specialize in treatment of HIV should understand differences in mutations caused by various antiretroviral agents. These include recognizing which drugs have common mutations that confer cross-resistance between other drugs, usually belonging with the same antiviral class. Additionally, the physician should know his or her patientГ•s HIV treatment history, to apply all the facts towards construction of a patientГ•s new antiviral regimen when and if they have developed resistance to their current treatment. Finally, if an individual had intolerable toxicities to a specific antiviral drug, decision-making is further influenced and one tends to avoid utilizing drugs that may provide similar toxicity. All of these and other factors are taken into account when constructing a patientsГ• regimen - after resistance has developed. However, now in the arsenal of weapons to help configure these new regimens, are tests that can help weed out some of the wrong possibilities. They include genotype and phenotype testing.

Genotype testing identifies the various mutations within an individualГ•s blood that are known to cause resistance to specific HIV drugs. The most efficient use of this test is taking a sample of a patientsГ• blood while they are on therapy but their viral load must exceed 1000 copies/ml. Remaining on therapy while the test is administered insures that mutant virus is present and can be captured for the test to be of greater accuracy.

Phenotype testing measures the virusГ• ability to replicate in varying concentrations of drugs in the test tube. Therefore, phenotypic testing should directly examine or test a patientsГ• HIV and their response to treatment with specific drugs. This test should also be performed while the individual is taking his current treatment regimen.

Although the development and utilization of resistance testing is a new milestone among HIV therapeutic armamentarium, there are various questions and unresolved issues regarding genotypic and phenotypic testing. Both tests show improved virologic outcome but no study has compared the two tests to demonstrate whether one test should be preferable over the other.

There are multiple studies recommending resistance testing for treatment failure. One instance of investigating the utility of the phenotype test was in the Vero 3001 trial. Here 274 patients who failed their first protease inhibitor regimen and could have had more than one set of nucleosides used in the past were studied. In this study the subjects had either their next cocktail chosen by either their physician or phenotype guided regimen. While there were various problems with the results of this study, including a high patient drop out rate from the trial, of the remaining analysis 38% of patients with phenotype guided regimens vs. 23 % of standard-of-care regimen showed viral loads less than 400 copies after 16 weeks. Therefore it may be concluded that patients in this circumstance would benefit having resistance testing done.

In other instances, such as in patients starting their first regimen, there are questions as to whether a resistance test should be preformed before starting initial therapy. There is the rationale to test someone who is recently infected since that individual may have been exposed to resistant virus. Having this knowledge can prevent failure of the first regimen only if there was exposure to resistant virus. However, there has to be resistant species predominating so that it can be measured. We have not been performing genotype or phenotype testing in naВ•ve subjects since we have not witnessed treatment failures of initial regimens thus far. Also chronically infected individuals but naВ•ve to antivirals often have predominant wild type virus (non mutated virus) so that the likelihood of isolating resistance is low. In this situation, the utility of this test is also limited.

Finally, in patients highly experienced to antiretroviral drugs, where no drugs are very active then the test will not be of benefit for an improved virologic response. One prospective study presented at the 7th Conference on Retroviruses and OIГ•s confirmed that no viral benefit was derived from the use of such tests at 16 weeks when compared to the standard of care (Melnick et al).

On the brighter side of resistance, various levels of resistance may or may not result in treatment failure. Often HIV specialists may use drugs that increase the levels of other antiviral agents so as to overcome resistance, as is the case with protease inhibitors. Additionally, it has been shown that even while there may be viral resistance occurring in a given patient on their regimen, the potency of HIV is reduced (despite the presence of resistance); this is sometimes referred to as reduced viral fitness. In other words, if viral fitness is reduced there is still benefit of resistant regimens in many patients. Notably, while viral resistance is rampant, opportunistic infections are rare and patients continue to do well with continued increases in CD4+ T cells (disconnect syndrome).

Nonetheless, we applaud the arrival of yet another weapon in which to combat HIV disease and effect better treatment through the use of resistance testing. There are indeed many instances for which to use either genotype or phenotype testing to assist in our ability in constructing better and more effective regimens for patients. However, more studies of using this relatively new test need to be completed.

Pipeline Mania
New and Promising Anti-HIV Drugs in Development

FTC

(Emtricitabine), a nucleoside reverse transcriptase inhibitor, presently is in phase III trials and appears to be very promising. FTC has activity against HIV, as well as, Hepatitis B. Addtionally, preliminary studies showed FTC to be more potent than 3TC with demonstrable 2.0 log drop in HIV RNA. FTC can be dosed once daily, but has a similar resistance profile to that of 3TC (184 codon mutation). and will probably replace 3TC.

PMPA Prodrug Protocol 902 (Phase 2) or Tenofovir DF

is part of a new class of reverse transcriptase inhibitors called nucleotides. It is active against HIV as well as Hepatitis B. PMPA is just completing phase II studies whereby the drug was found to be both safe and effective. In an earlier study of PMPA prodrug administered to monkeys demonstrated 100% prevention of infection with simian immune deficiency virus. PMPA prodrug has a very long half life and can be taken once daily, with food (since itsГ• bioavailability is increased to 40% with food). This agent also appears to be synergistic with other antiviral agents and has shown increased susceptibility to virus resistant to AZT, ddI, ddC and a two fold increase in susceptibility to 3TC resistant virus. Additionally, preliminary information regarding prior exposure to Preveon (adefovir dipovoxil) does not affect susceptibility. Thus far, the drug appears to have little side effects nor any nephrotoxicity (kidney). We believe that PMPA looks to be one of the most promising drugs to be coming along in a while. Phase III trials have recently started and is actively enrolling at NorthStar Medical Center. For further information call Harriett Wittert at (773) 296-2400.

MKC-442

(Emivirine) is a non-nucleoside reverse transcriptase inhibitor. Clinical trials have tested MKC-442 in combination with various antiretroviral agents and in salvage situations, patients failing protease inhibitors. This drug also appears to be more potent than nevirapine. Although it was found to be effective in earlier studies, itsГ• effect during for salvage situations was not impressive.

ABT-378r

This is Abbott Labs second generation protease inhibitor. The drug is formulated to include a small amount of ritonavir with each capsule, in order to increase itsГ• levels in the blood stream. The drug is hoped to be effective against some protease inhibitor resistant virus and therefore may be useful in salvage situations. However, the reasoning by Abbott Labs of itsГ• use for salvage was somewhat based on a particular clinical study and is problematic. This study utilized ABT-378r with non-nuc naive and dual- protease inhibitor naive subjects in a five drug regimen. In summary, while the results showed good viral suppression, the contribution of ABT-378r to this regimen is impossible to discern. Additionally, we believe that this drug should be studied in patients with extensive dual protease inhibitor and non nucleoside experienced patients, so that itsГ• use for the most common salvage situation can be better understood. Currently available on a compassionate access program, the drug is expected to come to market by the fall of 2000.

Lodenosine

(F-ddA) is a fluorinated nucleoside reverse transcriptase inhibitor (NRTI) that is long acting and has a half life of 20 hours making dosing once a day possible. Additionally, and very importantly, it is active against many of the NRTI resistant virus including the Q151M mutation which confers high level of resistance to multiple nucleosides. Therefore it appears to be useful for patients in salvage situations or patients failing other available cocktails (or in whom have extensive NRTI exposure). A recent and ongoing study has examined F-ddA in combination with d4T and indinavir (Crixivan). Early indications are that this combination is active with potent anti-HIV activity. However, there have been some serious adverse events associated with the US Bioscience sponsored trial. Thus further plans for the future development of lodenosine is on hold until clarrification of these adverse events and their relation to the drug is made.

DMP 961 and DMP 083

Dupont PharmaceuticalsГ• second generation non-nucleoside reverse transcriptase inhibitor (NNRTI), DMP 961, was set to undergo phase III studies. However, the drug has now been placed in a holding pattern. The decision to change gears was due to some drug interaction and pharmakokinetic studies, as well as concern that 961 may not be as advantageous as previously thought for salvage situations. Alternatively, Dupont will go ahead in evaluating another NNRTI, DMP 083, which may have a better profile. Dupont Pharmaceuticals Company is committed as developing an NNRTI that will be unique in providing superiority in effect for patients that have been highly exposed to most other approved agents.

T-20 and T-1249.

These drugs are of great interest and an exciting development in treatment for patients that are highly experienced to treatments. They belong to a new class of therapy called fusion inhibitors, because they block binding of HIV onto the receptor on the CD4 T-cell. Preliminary studies have shown that T-20 was effective in patients with resistance to other antiviral agents. Cross resistance is unlikely, due to the unique mechanism of action. Currently T-20 is administered by subcutaneous injections twice daily. The drug was developed by a small biotech company called Trimeris but was recently also acquired by the large entity, Roche Pharmaceticals, which will aid in itsГ• faster development and production..

L2 form of Interleukin 2

This is Chiron PharmaceuticalsГ• new formulation of Interleukin 2. This new monomeric version is touted as being three times more potent as the original version and because of itsГ• chemical structure is expected to have less side effects, especially at the injection site ( IL2 is normally administered by subcutaneous injection). The drug is currently undergoing phase I and II studies.

GW420867X

non nucleoside that appears to be very potent in itsГ• antiviral effect. Furthermore GW420867x has a long half life thus making for once daily dosing. ItsГ• other attributes include low drug interactions, since itsГ• metabolism is via different pathway than protease inhibitors.

Tipranavir

is a new and novel protease inhibitor developed by Pharmacia Upjohn. However, the drug has been recently acquired by Boehringer Ingelheim which we believe will allow for itsГ• faster development and use. This protease inhibitor is in a new class being non-peptidic, does appear to be unrelated chemically to other available protease inhibitors with a different resistance profile. In itsГ• current formulation one needs to take 10 large pills three times daily. As a result the drug is being studied in combination with ritonavir, thus reducing frequency of dosing and pill burden.

dAPD

is a nucleoside reverse transcriptase inhibitor that is being developed by Triangle Pharmaceuticals. Chemically related to abacavir (Ziagen), because of it being a guanosine analog, has also potent activity against HIV as well as Hepatitis B. In-vitro (test tube) studies have demonstrated similarities in resistance mutations to ddI, ddC and abacavir.

The latest FAT Facts & Abnormal Changes in Body Composition

By Daniel S. Berger MD, FACN

Attending the 3rd International Conference on Nutrition and HIV Infection in Cannes, France was quite an experience. One doesnГ•t routinely expect to be at an AIDS conference on the French Riviera. But the meeting was an excellent display of 300 international specialists uniquely involved in helping to develop our understanding of new metabolic complications of HIV treatment and itsГ• clinical concerns. Additionally a satellite symposium was held to discuss immune reconstitution in HIV.

Looking back, it has been quite a journey participating in the research for the development of HIV treatments; the field of nutritional intervention has evolved alongside. In many ways we have developed a greater understanding of body composition and nutritional management. Five to 15 years ago we were involved in better defining wasting syndrome and treatment. Only three years ago, and after the widespread use of protease inhibitors, one thought that nutritional problems and wasting was nearly conquered. Now, however, we are left with a completely different picture of unanswered questions. HIV specialists and scientists are actively engaged in researching the various factors that influence the metabolic and fat redistribution changes that seemingly have become complicatedly prevalent and upsetting amongst our patients. This third international conference in Cannes was organized to encompass new data on the impact that protease inhibitor containing regimens have on body composition changes, alterations in lipid and glucose metabolism as well as hormonal aberrations.

What's in a name?

There have been many different names to describe the body compositional changes among HIV positive patients. They include Lipodystrophy Syndromes (LS), fat accumulation, protease paunch, Crix-belly, fat redistribution, buffalo hump, HIV-Associated Lipodystrophy or HALS as well as fat depletion. Some patients are developing various manifestations but in mixed and variable degrees. (Please see the previous issue of AIDS INFOSOURCE for a more detailed description).

Are Antivirals the Cause?

Some studies have retrospectively looked at antiviral drug regimens to elicit any associated or contributing factors. While an Australian group has ascribed the changes occurring from protease inhibitor use, there have now been many reported cases of patients never treated with these agents who also manifest these abnormalities. Additionally at this conference, Dr Thierry Saint Marc from Lyon, France presented data that attempts to associate d4T use to programmed cell death of adipose tissue (fat cells). An investigator from Westminster Hospital of London, Dr. Bria Gazzard, looked at patients on non-nucleoside (NNRTIГ•s) drugs and presented data showing no associated relationship to the NNRTI, delavirdine.

Dr Esteban Martinez from Barcelona Spain had examined a group of patients who developed fat accumulation and subsequently taken off their protease inhibitors in exchange for a non-nuc, nevirapine. The early data showed a trend towards improved body composition changes, while maintaining their viral loads below the level of detection. Moreover, we (NorthStar Medical Center) are currently enrolling patients for a new study (DMP-049) that looks at body composition changes and the safety and effect of exchanging therapy of protease inhibitors for Sustiva. More studies should be done with this approach.

A large study was presented involving more than 200 patients, who filled out a 19 page questionnaire with their companion physicians completing another 16 pages of questions. This SALSA study (Self-Ascertained Lipodystrophy Syndrome Assessment) attempted to define lipodystrophy syndromes and itsГ• prevalence. Dr. Norma Muurahainen presented their findings that described 85% of patients with fat accumulation and 73% with fat depletion. Additionally, the majority of patients also described a mixed picture, whereby they had areas of their body showing accumulation and other body parts with depletion. There was a strong correlation to patientsГ• and their physiciansГ• assessment of their body composition changes.

Male vs. Female

Several studies presented attempted to discern specific gender differences to the lipodystrophy syndromes. Dr. Julian Falutz from Montreal discussed gender associated differences among his cohort of patients, whom the overwhelming majority were at undetectable viral loads and had moderate CD4-T cell changes. Falutz observed that men showed more fat depletion while the women were more apt to demonstrate accumulation. Blood lipid abnormalities were also common among all patients but were more frequent among patients with fat lipodystrophy syndromes. Dr. Kathleen Mulligan from the University of California at San Francisco studied women with fat redistribution, demonstrating breast enlargement and truncal obesity being the most common manifestation. However, it was also observed that many also had fat loss in the buttocks, calves and thighs.

Treatment?

Dr Christine Wanke from Boston reported 10 patients on protease inhibitors with fat redistribution who were then treated with growth hormone for 12 weeks. These patients demonstrated decreases in abdominal or waist-to-hip ratios while increasing thigh measurements. Other researchers at the Cannes meeting described anecdotal reports of patients with fat accumulation who were treated with growth hormone because of buffalo humps or abdominal fat increases and one report was of a man with a large accumulation of fat on his head. These patients were treated with recombinant human growth hormone and showed improvement in their fat accumulation condition.

Other Complications

Among some of the various metabolic complications of HIV therapies lipid disorders appear to be highly prevalent. Elevations in triglycerides, cholesterol and decreased HDL cholesterol have been reported. While the true clinical significance of these are controversial, case reports of coronary artery disease in HIV positive individuals have been surfacing. This Chicago author reported on a cohort of 19 patients, most of whom also had some component of lipodystrophy, and 50% had elevations in cholesterol or triglycerides. 17 of 19 patients had to be treated for new onset hypertension (high blood pressure) and 4 patients developed coronary artery disease (3 of whom subsequently underwent angioplasty. Interestingly, many of the patients had a history of anabolic steroid use and therefore questioned whether anabolic steroid use contribute to new onset hypertension in patients with added risk factors.

Dr. Mary Romeyn from San Francisco reported on a small group of 17 subjects. 13 of 17 demonstrated a loss of bone density and 6 of the 17 had osteoporosis. This patient group was largely very immune compromised, with CD4 + T cell counts below 100 cells but without any history of immobilization or corticosteroid use.

Another metabolic abnormality has been the development of insulin resistance and can often lead to elevated sugar levels (hyperglycemia) and diabetes. Diet and exercise is the mainstay of treatment but drug therapy may sometimes be indicated. Drugs such as troglitazone (rezulin) and metformin (glucophage) as well as insulin have been used. Saint Marc from France reported a small group of patients who were treated with metformin with resultant decreased body fat, visceral adipose tissue and reduced waist-to-hip ratios. Further studies with metformin should be done.

Summary

In summary, progress in this relatively new field of body composition problems and associated metabolic abnormalities is underway. However, the etiology of fat redistribution still remains elusive while the research is barely scratching the surface. Hopefully, further studies to expand our knowledge in this area will result in new interventions and treatment for the not-too-distant future.

HIV Positive Women Have Higher Risks for Developing AIDS.

Researchers from JohnГ•s Hopkins have demonstrated that HIV-positive women with similar viral loads of males appear to have half the CD4 T cell counts of their male counterparts. Women may not be equal in HIV progression due to hormonal, biologic or anatomical differences. Other researchers in Switzerland and Italy have reported similar results. It may be inferred that HIV+ women should be treated more aggressively and earlier.

HIV Suppression vs. HIV Cure.

Researchers and physicians have been pendulum swinging from two vantage points. The hope of finding a cure via focused research on the treatment of latent (inactive) virus populations is tempered with the struggle of keeping HIV under control. Obstacles of resistance and trying to help promote adherence to difficult treatment regimens for some patients is a frequent daily labor for physicians and patients alike. Most believe that finding a cure is still a surmountable task that can be undertaken. While every HIV infected cell in the body may not be reachable with current antiviral drug therapy, there may be ways to strengthen the immune system to overcome HIV.

Cigarette Smoking.

A New study has revealed that smoking may be an additional health risk for HIV infected patients. The study published in the American Journal of Respiratory and Critical Care Medicine demonstrated that HIV-positive individuals who smoke have depressed levels of CD8-lymphocytes in the bronchial lavage fluid which may play a role in fighting HIV. Smokers were also shown to have lower levels of interleukin-1 in the bronchial fluid, important at fighting bacterial infections. The study may suggest and explain how HIV-positive smokers are more at risk for respiratory and lung infections such as bronchitis and pneumonia.