On October 12, 1999 the University of California San Francisco (UCSF) - Gladstone Institute of Virology and Immunology held their 5th Annual Translational Research Symposium. The theme of this year's meeting was Deciphering the Biology of HIV for Prevention and Treatment. The following are summary highlights from the meeting.
Throughout her talk, Dr. Chesney emphasized that controlling the AIDS epidemic is fundamentally a multidisciplinary concern. That is, preventing the transmission of HIV and slowing progression to AIDS in those living with HIV involves examining basic science, medical science and behavioral patterns in both people living with HIV as well as those who are HIV-negative but at risk. Some preliminary findings from the behavioral research component of the Options Project include:
People enrolled in the study who elected to start anti-HIV therapy were not always adhering to treatment regimens, and researchers attribute this to the practices of individuals as well as to the practices of some doctors. The time a physician takes to work with a patient and explain the demands and importance of adherence is a factor influencing a person's willingness and ability to adhere. Dr. Chesney suggests that doctors can help to enhance a person's willingness and ability to adhere to the demands of anti-HIV therapy regimen by:
Simplistically, if the immune system developed a response to effectively target gp120, then the key could never be put in the door and HIV could not get into immune cells. Hoxie's work has tried to shed light on why the immune system is not able to develop this effective response. He has found that the most important part of gp120 (the constant region) is hidden from the immune system. Covering this region is an ever-changing mask (called the variable region). The immune system sees this ever-changing part of gp120 and mounts a response. This response has little to no effect, however, on the more critical, constant part of gp120 that allows it to enter an immune cell.
It's possible that if researchers could develop a way to enhance the immune system's ability to see the constant region of gp120 and mount or induce an immune response, new directions in HIV treatment and prevention research may emerge.
There are different "types" of HIV, notably one type that uses the CCR5 "co-receptor" to infect CD4+ cells. The other uses the CXCR4 co-receptor to infect CD4+ cells. The type of HIV that uses the CXCR4 receptor to infect cells is more aggressive. Studies suggest that when it becomes predominant in an individual, there is an increased loss of CD4+ cells and a more rapid progression of HIV disease. A question that remains unanswered is why, in some people, this aggressive virus becomes predominant and why the less aggressive, CCR5-dependent virus remains more prominent in others. Dr. Goldsmith's research begins to shed light on this issue. (For more information about co-receptors and their role in HIV infection, call the Project Inform Hotline and ask for the Co-Receptors Discussion Paper).
Dr. Goldsmith wanted to find out whether this shift from one type of virus to another more aggressive type was a cause or a consequence of HIV disease progression. His preliminary findings suggest that this shift may be a consequence of the disease and may not be driving disease progression. He explains this by noting that the less aggressive kind of virus (the CCR5-dependent virus) is produced, generally, in greater quantity than the aggressive kind of virus (the CXCR4-dependent virus). This lopsided production may explain why the less aggressive type has been observed as the predominant virus in people who are healthy and in earlier stages of HIV disease progression. Since the less aggressive form of HIV is present in greater quantity early on in HIV infection, the majority of immune cells will be infected with the less aggressive form during this stage. As time goes by, the cells that produce this form of virus may be the first to be destroyed, both as a result of direct infection by HIV as well as by other immune mechanisms. Eventually, the cells that produce the more aggressive form of virus that is slower growing, may be all that remain. So while it has been believed the change in virus was driving disease progression in some people with advanced disease, Dr. Goldsmith's research suggests that this may simply be a consequence of the status of their immune system. In other words, when cells that produce the less aggressive form of virus are significantly decreased in number, only cells capable of producing the more aggressive virus may persist.
Further research is needed to verify Dr. Goldsmith's conclusions. These preliminary findings, however, may offer a glimmer of hope for people with advanced-stage disease who have this more aggressive (CXCR4-dependent) form of virus. If HIV levels can be brought under control, and the immune system experiences recovery, it is likely that the less aggressive virus may once again dominate. AMD-3100, a new anti-HIV therapy, may selectively target and inhibit this more aggressive form of HIV. For more information, see PI Perspective #28.
Dr. Goldsmith also introduced some research on the differences and similarities between HIV-1 and HIV-2. HIV-1 is the kind of HIV found most commonly throughout the world. HIV-2 is found uniquely in certain parts of Africa. A study has shown that women in Africa infected with HIV-2 are not as likely to progress to AIDS as are people infected with HIV-1. The interesting finding is that not many fundamental differences were found between the two kinds of virus. Furthermore, the two kinds of HIV were shown to reproduce as efficiently in human tissue studied outside of the body. Thus, by studying HIV-2 and trying to understand why people living with HIV-2 may progress to disease more slowly may shed light on new directions for treating HIV-1.
Dr. Luban and his associates looked at mice that could not produce their own CPA and infected them with HIV. They noticed that, overall, the health of the mice were not negatively affected by the lack of CPA. However, the absence of CPA in the mouse's body had a significant effect on HIV's ability to reproduce. The mice infected with HIV that lacked the ability to produce CPA seemed to have a reduction, but not elimination, in the amount of HIV in their blood. Therefore, Dr. Luban suggests that CPA is important for HIV replication, but it is not essential. Certainly some HIV was able to persist even though CPA was not present.
Dr. Luban and his associates performed some other experiments to figure out exactly how CPA effects HIV replication in our bodies. They suggest that CPA does not interact directly with HIV. Rather, CPA works with other chemicals in our body to alter and weaken our own immune response to HIV infection. In particular, Luban's work suggests that CPA, interacting with other immune factors, influence a shift in the immune response from a T-helper type 1 (TH-1) response to a T-helper type 2 (TH-2) response. This may be an important discovery because the TH-1 response is believed to be important for the natural immune control of HIV.
Dr. Luban's research is still at an early stage, but more investigation on the function of CPA may help identify immune factors and dysfunction associated with HIV disease progression. Some of these have been identified, but clearly not all. Eventually, his work may lead to therapies which inhibit CPA or other cellular factors needed for HIV to reproduce.
Dr. Hunter discussed some new developments and concerns regarding the experimental anti-HIV drug T-20 (pentafuside), which is a "fusion inhibitor", blocking HIV entry into cells. Specifically, Dr. Hunter discussed the current drawbacks to T-20 therapy. In particular, there have been strains of HIV found to be resistant to T-20. Also, since T-20 is a protein, it can't be taken orally because the stomach will digest it before it can get into the bloodstream. At the moment, it can only be given as an injection under the skin (called subcutaneous injection) and unfortunately that is unlikely to change in the near future. There is also a concern that the body can develop an immune response against T-20 and eliminate it before it can do its job. Even so, studies are ongoing to better determine the safety and effectiveness of T-20 therapy. For more information on T-20 (pentafuside), see PI Perspective #28.
Overall, this session addressed many important concerns about immune function in people living with HIV. The interaction between HIV and the immune system is complex, and a great deal more has to be done to understand it better. And a better understanding of this interaction can then lead to the development of therapies down the road that enhance immune restoration.
Dr. John's study evaluated the frequency of HIV transmission through breast milk and whether formula-feeding was a good alternative to breast-feeding for children of women living with HIV. Her study was conducted in Nairobi, Kenya. In the study, 425 pregnant women living with HIV were instructed to only breast-feed their child or were told to only formula-feed their child. There were 401 infants who were monitored from birth until the age of two.
Of the children fed breast milk only, 61 became infected with HIV, whereas 31 of the children fed only formula became infected. They also determined that transmission occurred early in breast-feeding. In terms of baby survival, Dr. John and her associates noticed no significant difference between the two groups. Forty-five of the children who were breast fed had died by the end of 2 years and 39 deaths occurred among children who were formula fed. As expected, the deaths among children who received only formula occurred soon after they were born when the immune enhancing properties in breast milk may have provided some protection from infections.
The deaths among children who were breast-fed, however, occurred later and most deaths were associated with HIV related complications.
Overall, 58% of the babies who were fed breast milk were alive and remained HIV-negative after 2 years whereas 70% of the babies who were fed formula were alive and HIV-negative at the end of two years. Dr. John calculated that, in her study, 16.2% of mother-to-child HIV transmissions were due to breast-feeding, and she suggests that her calculations may be low and that breast-feeding may pose an even greater risk to the child than her study suggests.
From her study, Dr. John concludes that formula feeding can prevent transmission of HIV from mother to child through breast milk. Even though baby formula lacks some important properties that breast milk has, that doesn't seem to outweigh the benefit that formula feeding has in preventing the transmission of HIV. And while formula feeding a child may be preferable for mother's living with HIV, formula feeding may still not be a realistic alternative for some women, especially in the developing world, because of a lack of resources, including money and clean water.
Dr. Hillier's work, therefore, suggests that N-9 is not an ideal microbicide for HIV prevention. A number of alternatives to N-9 are currently undergoing study.
Although treatment advances in the developed nations have not been shared by third world countries, successes in prevention efforts have made some headway. One strategy for prevention employed by Dr. Allen's group included the use of HIV testing and "voluntary couples counseling". HIV testing now costs a little less than a dollar per test, and has become more available in Africa. Resource intensive, voluntary couples counseling (counseling of sex partners accompanying joint HIV screening) has apparently been helpful in stemming the tide of new HIV infections. Of more than 15,000 couples counseled in two countries in Africa, over 4,800 people were newly diagnosed with HIV and, according to Dr. Allen, over 2,000 new infections were prevented. Couples counseling informed couples of their HIV status, together. In cases where one partner was HIV-positive and the other HIV-negative, information and prevention messages delivered to both partners, together, may decrease risk-taking behavior and prevent HIV transmission. According to Allen, this voluntary couples counseling approach was effective.
Couples counseling is not widely used in developing countries because of high maintenance costs for the program (that is, it's not a one-time cost) and because third world countries are increasingly prioritizing prevention efforts directed towards youth and children. Nevertheless, Dr. Allen suggests that in light of her findings on the effectiveness of couples counseling, a combination of this approach with antenatal clinics (i.e. clinics used to help prevent transmission of HIV from mother to child) could help to control the AIDS epidemic in developing countries.
The political instability and limited resources of third world countries hinder the realization of truly effective and accessible prevention and treatment programs. Incremental improvements to treatment and prevention programs are critical toward improving the lives and quality of life of people affected by HIV/AIDS in the third world. Indeed, about 80% of all people living with AIDS, worldwide, are in Africa. Designing and improving programs to help people effectively deal with HIV disease within the limitations of their environments (and pushing the envelope of the limitations) would significantly alter the course of the epidemic in developing nations.
FDA has published a Public Health Advisory for health care practitioners to remind prescribers of important and therapeutic considerations when treating patients with influenza-like symptoms. Influenza is now occurring in many areas of the country, and healthcare professionals are confronted with therapeutic decisions for large numbers of patients with flu-like symptoms. Among other factors, they may consider whether to use one of the four drugs currently approved for antiviral therapy in uncomplicated influenza. Two of these, amantadine (Symmetrel® and others) and rimantadine (Flumadine®), have been available for some years in the United States for illness due to influenza A. The recent approval and current promotion of two additional drugs with activity against influenza A and B, zanamivir (Relenza®) and oseltamivir (Tamiflu®), has increased interest in the role of specific antiviral drugs for this disease.
While healthcare professionals and consumers are becoming familiar with the treatment options, FDA's advisory provides several considerations for health care professionals treating flu patients.
Antiviral products such as those approved for flu have no activity against bacterial infections and patients should be treated with appropriate antibacterial therapy whenever bacterial infection is suspected. FDA has received reports of patients with serious bacterial infections who initially had influenza-like symptoms and who had progression of bacterial infection during treatment with antiviral drugs alone. Prescribers should also be aware that antiviral drugs have not been proven to prevent or effectively treat viral complications of influenza such as viral pneumonia. Antiviral drugs for treatment of influenza have only been shown to be effective if started in the first two days of symptoms, and the demonstrated treatment benefit has been limited to a modest increase in the rate of symptom improvement.
FDA has received reports of respiratory problems following inhalation of Relenza. The Relenza package insert contains important precautionary information regarding risk of bronchospasm in patients with respiratory disease If a decision is made to use Relenza in patients with airway disease (e.g. asthma), this should be done only under careful supervision and with adjunctive care including short-acting bronchodilators available.
FDA encourages patients to ask questions and to make themselves familiar with the complete prescribing information when considering flu drugs. The labeling for all four flu drugs includes summaries of adverse events observed during clinical trials, as well as post-marketing experience for the two drugs with a longer marketing history. As with all drugs, FDA encourages all health care professionals to report any serious adverse event associated with the use of antiviral drugs for influenza to the FDA's MedWatch program at 1-800-FDA-1088 (fax 1-800-FDA-0178), or to the pharmaceutical manufacturers:
The following letter has been distributed to healthcare professionals regarding the use of flu drugs:
|Food and Drug Administration Public Health Advisory Subject:|
Safe and Appropriate Use of Influenza Drugs
Diagnostic and therapeutic decisions for patients with symptoms of influenza involve many factors, including consideration of whether to prescribe one of the four drugs currently approved for treatment of influenza. Two of these drugs, amantadine (Symmetrel® and others) and rimantadine (Flumadine®), have been available for many years in the United States. The recent approval of, and promotional activities for, two additional drugs, zanamivir (Relenza®) and oseltamivir (Tamiflu®), have increased attention to, and interest in, the role of specific antiviral therapy in this disease.
Given that influenza is now occurring in many areas of the country, FDA is issuing this public health advisory to health care professionals to remind prescribers of important clinical decisions that need to be made when considering use of anti-viral drugs for treatment of patients with signs and symptoms of influenza. The following three considerations are important primarily for two reasons. First, they are important in identifying patients who are appropriate candidates for anti-viral therapy. Secondly, they are important in recognizing patients who may be at risk for serious adverse outcomes from other non-influenza diagnoses or from adverse events potentially related to anti-influenza therapy.
FDA has received several reports of patients with serious bacterial infections who initially had influenza-like symptoms and whose bacterial infections progressed during treatment with antiviral drugs alone. Prescribers should be aware that patients with severe influenza-like illness, especially patients with chronic medical conditions or complicated manifestations of acute illness, might have significant bacterial infections instead of, or in addition to, viral illness. These anti-viral products have no activity against bacterial infections. Appropriate anti-bacterial therapy should be initiated whenever bacterial infection is suspected.
Use special caution if prescribing Relenza® to patients with underlying asthma or chronic obstructive pulmonary disease (COPD). FDA has received several reports of deterioration of respiratory function following inhalation of Relenza® in patients with underlying asthma or COPD. Causal relationships with drug therapy are extremely difficult to evaluate in the setting of complex medical processes, but the possibility can not be excluded that an acute decline in respiratory function may contribute to a fatal outcome in patients with a complicated pre-existing medical history and pulmonary compromise. The Relenza® package insert contains important precautionary information regarding risks of bronchospasm in patients with underlying airway disease and regarding the lack of proven efficacy in such persons. If a decision is made to prescribe Relenza® for a patient with underlying airway disease, this should be done with careful consideration of the potential risks and benefits. In such patients, Relenza® should be used under conditions of careful monitoring, proper observation and appropriate supportive care, including the availability of short-acting bronchodilators.
The evidence for use of antiviral drugs to treat influenza is based principally on studies in patients with uncomplicated influenza. There is not clear evidence for safety and efficacy in persons with underlying respiratory or cardiac diseases, or in persons with complications of an acute influenza episode (for example, viral or bacterial pneumonia). Such patients may require extensive supportive and adjunctive care. Anti-viral therapy has not been shown to reduce the need for such care and monitoring. All health care professionals are encouraged to report any serious adverse event associated with the use of anti-viral drugs for influenza to the FDA's MedWatch program at 1-800-FDA-1088 (fax 1-800-FDA-0178), or to the respective pharmaceutical manufacturers.