The introduction of antiviral medications used in combination is among the most important advances in the history of HIV/AIDS treatment. By using more than one drug at a time, combination therapy is able to "pin down" HIV from more than one angle, so that even if one drug fails, another can continue to suppress viral replication. But this advance was a long time in the making, following a historical course from "no therapy" to "monotherapy" and now to "combination therapy." This book excerpt provides a historical overview of advances in the monitoring of treatment progress and the emergence of combination therapy.
In the Beginning
In the summer of 1981, Mortality and Morbidity Weekly Report, published by the U.S. Centers for Disease Control and Prevention (CDC), included two reports about increases in previously rare infections among gay men in the New York and California. "Physicians should be alert for Kaposi's sarcoma, [Pneumocystis carinii] pneumonia, and other opportunistic infections associated with immunosuppression in homosexual men." Thus began a process of medical discovery about Acquired Immunodeficiency Syndrome (AIDS) which continues to the present day.
Although medical progress has often seemed slow in coming, advances in knowledge about AIDS have in many ways actually been swift. Within a year, epidemiological evidence had made clear that the causative agent of AIDS was sexually transmissible, and that it had particularly spread within sexual networks of gay men. Within two years, advances in the then-nascent field of retrovirology enabled researchers at the Pasteur Institute in Paris to isolate the "AIDS virus," which eventually came to be known as the Human Immunodeficiency Virus or HIV.
Further research gradually determined the precise means by which HIV invades the human body. Transmitted from person to person primarily through blood, semen, and vaginal secretions, HIV's principal targets are the very cells of the immune system (particularly CD4+ t-cells and macrophages) which are intended to clear foreign pathogens from the body. After entering a cell of the immune system, the virus begins a relentless process of replication, its sole activity and one which allows for a constant spread to new cells. In the process, the immune system of the host organism can be devastated.
Whereas most viruses retain their genetic information on strands of DNA, retroviruses like HIV employ simpler RNA. The virus's outer coat consists of particular glycoproteins, which can form biochemical bonds with particular proteins (such as CD4) that are found on the surface of some cells, notably those in the immune system. Once bonding occurs, the HIV life cycle requires the insertion of its own genetic material into the host cell and ultimately the use of three important viral enzymes. The first, reverse transcriptase, converts RNA into DNA (a process called "reverse transcription"). The second, integrase, integrates the viral DNA into the human cell's DNA. The third, protease, later cleaves off new copies of the viral proteins, allowing new virus particles to be assembled and enabling these new viruses to leave the cell. These three enzymes are essential to the process of viral replication, and most advances in HIV treatment have come from inhibiting the activity of these enzymes.
From Monotherapy to Combination Therapy
In 1986 the U.S. Food and Drug Administration (FDA) approved the first antiviral drug zidovudine (ZDV; AZT) for use in preventing HIV replication by inhibiting the activity of the reverse transcriptase enzyme. AZT is part of a class of drugs formally known as nucleoside analog reverse transcriptase inhibitors. After 1991, several other nucleoside analogs were added to the anti-HIV arsenal, as were a new class of anti-HIV drugs called the non-nucleoside analog reverse transcriptase inhibitors which work in similar ways to the nucleoside analogs but which are more quickly activated once inside the bloodstream. Next to be developed were the class of antiviral drugs known as protease inhibitors, which were distinctly different from the reverse transcriptase inhibitors in that they do not seek to prevent infection of a host cell, but rather to prevent an already infected cell from producing more copies of HIV.
Despite this proliferation of drug options, the standard antiviral therapy for HIV-infected individuals between 1986 and 1995 for the most part remained "monotherapy" or treatment with a single drug. Such drugs appeared to be partly efficacious, although there was a great variation in effectiveness among individuals.
During this period, there were also significant advances in the understanding of how HIV functions in the body. In particular, whereas it was once believed that individuals went into a latency period of ten years or more after their initial infection with HIV, it came to be understood that huge amounts of viral replication continued throughout the entire period of infection, even if an individual was not exhibiting any symptoms of illness. Thus, the onset of symptoms of AIDS is now known to be the result not of a sudden resurgence of a latent virus, but rather of a slow "war of attrition" between HIV and the host immune system, with the latter slowly being whittled away by the former.
The recognition of the persistence of viral replication -- with billions of copies of HIV being produced and destroyed daily -- also made possible a better understanding of the process by which the virus gradually becomes less sensitive to specific antiviral medications, a process known as developing resistance. Such resistance generally occurs when a random mutation during the replication of HIV causes a small genetic change in the virus's RNA, in the process making it less vulnerable to the effects of antiviral drugs. Drug resistance can seriously complicate treatment by rendering drugs less effective or even completely ineffective. Further, once an organism has developed resistance to one drug, it can also become resistant to other drugs in the same class (cross-resistance) or to a number of different drugs (multidrug resistance).
From this perspective, it could be seen that monotherapy against HIV was of limited usefulness because HIV could quickly develop resistance to any one medication. However, the expansion of the number of distinct classes of antiviral medications made possible a shift from monotherapy to combination therapy, in which drugs from two or more classes are used simultaneously. This switch to combination therapy has had dramatic effects because "in essence, combination therapy suffocates mutated forms of HIV before they have a chance to flourish. For example, in a combination of ddI, d4T, and indinavir, a strain of HIV that is naturally resistant to ddI will be kept in check by d4T and indinavir, while a strain of HIV that is resistant to indinavir will be kept in check by d4T and ddI" (Horn 1998). When nucleoside analog drugs, the non-nucleoside analog drugs, and the protease inhibitors are used in concert, these drug combinations are referred to as "highly active antiretroviral therapy" or HAART.
HAART has been prescribed by physicians in a wide variety of combinations, and, over time, convincing evidence has emerged that particular combinations of one protease inhibitor and one or two other drugs can have dramatic effects, reducing the amount of virus in the blood, prompting an increase in the number of CD4+ cells, and leading to improved health and well-being and minimizing the opportunity for new mutations which might create drug-resistant strains of HIV. By the start of 1997, combination therapy had become the standard of care for HIV-infected individuals who have begun to exhibit signs of significant immunosuppression, although no clear cut consensus has emerged about the best time to initiate therapy. This decision must be based on balancing a variety of factors including the length of time since initial infection, current CD4 cell count and viral load, clinical prognosis, side effect profile, and the individual's psychological readiness and motivation to begin and adhere to treatment.
Still Not a Cure
In all, the simultaneous treatment of people with HIV with different classes of antiviral drugs is among the most significant scientific advances in the history of the AIDS epidemic. Five years after its widespread use, combination antiviral therapy has demonstrated enormous potential, eliminating early fears that it would prove to be yet another dead-end in the treatment of HIV infection. On the other hand, however, combination therapies have not yet achieved the most optimistic goals set by scientists, much less the often-hyped claims of the popular media. In particular, the complete elimination, or "eradication," of HIV from an infected individual has never been achieved, and perhaps may never be achieved because HIV has the capacity to remain dormant in certain cells and also to infect difficult-to-reach cells in the central nervous system and other parts of the body. Similarly, antiviral medications have the characteristic of allowing full or partial resistance to develop after even a week of missed medication, irregular use, or incomplete doses, and cross-resistance is very common.
Nonetheless, the overall impact of combination therapies has been overwhelmingly positive. Since the mid-1990s there has been a significant decline in death rates from AIDS in the United States, as well as in new AIDS diagnoses and in hospitalizations for HIV/AIDS-related complications.
This decline in AIDS deaths has been attributed to a variety of causes, including improved treatment of and prophylaxis against opportunistic infections as well as a long-projected epidemiological drop-off as the huge first wave of people infected with HIV in the 1970s or early 1980s died in the early to mid-1990s. However, the introduction of combination therapies has also played a crucial role in this decline. Indeed, combination therapies have brought numerous individuals back from the proverbial "brink of death," restoring many thousands to a semblance of their earlier health and sharply reducing incidence of new HIV-related opportunistic infections and cancers. It appears this trend of declining deaths will continue, though because the advances in treatment have been only available for a relatively short time, no one can say for certain what the long term effects of these treatments will be. Long term use of antivirals may provide a window of opportunity for immune-boosting therapies and perhaps even restoration to normal immunological functioning. On the other hand, continued use of these powerful, toxic medications presents complicating factors of its own -- notably damage to vital organs such as the liver, kidneys and heart.
Another, more subtle, measure of the influence of combination therapies has been made possible by new assays such as the polymerase chain reaction (PCR) and branched DNA (bDNA) that measure viral load, or the number of circulating viral RNA copies in the blood. Previously, clinicians were forced to rely upon the CD4+ cell count as the principal "surrogate marker" for the efficacy of antiviral treatment. Now, however, viral load has been shown to be more reliable in monitoring treatment and also has been associated with progression of HIV disease: in general, the higher the viral load, the more rapid the progression of illness. In short, while CD4+ cell count can help with a diagnosis of how the patient is currently doing, CD4+ cell count and viral load together can help form a better prognosis of likely future outcomes.
Viral load tests are used to monitor the success of treatment and to suggest when a particular combination therapy is not working. Successful treatment often leads to a viral load reading "below the level of detection" (formerly, and somewhat confusingly, known as "undetectable"), indicating that the concentration of HIV in the blood is too low to be detected using a particular assay. Depending upon the assay, this may range from less than 500 to less than 40 copies of viral RNA per milliliter of plasma. While a viral load below the level of detection is an affirmation of good health, it emphatically does not mean that the blood is virus free or that viral load will remain low over time. Further, studies have shown that people who have viral loads below the level of detection in the blood may have virus in the semen or vaginal secretions which means that they remain potentially infectious.
When HIV develops resistance to a particular drug or combination the virus is said to "breakthrough" and viral load begins to rise. At this point, the provider usually recommends a new set of antiviral drugs. Choosing the new combination is a complex matter since issues of cross-resistance must be taken into account. Thus, while switching is possible, the number of times a change in regimen can be made is limited, and the potential of exhausting these limited options makes many people reluctant to change medications.
The Post-Vancouver State of Combination Treatment
Overall, for people living with HIV disease, as well as professionals working with them, the news about the effectiveness of combination therapies that emerged in 1996, particularly from that year's International AIDS conference in Vancouver, was heartening but also confusing. During and after the conference, mainstream media reporting made it seem as if a total cure had been discovered.
Following the conference, a spate of news coverage suggested an end to the epidemic. An article by Andrew Sullivan in the The New York Times Magazine was called "When Plagues End: Notes on the Twilight of an Epidemic," an overly optimistic title that reflected the tensions surrounding advances in treatment. There finally seemed to be a reason to hope that HIV disease might become a chronic and manageable illness for more than a small minority of those infected. Yet to proclaim that we were entering the "twilight of the epidemic" gave false hope, is and was misleading (especially for people without any access to treatment). While combination therapy does not eliminate HIV from the body, the virus only slowly develops resistance to the drugs in people who follow the strict schedule of medicine. This means that people who benefit from combination therapy cannot safely discontinue their strict schedule of medications without experiencing a rebound in viral activity. (There is research currently underway, however, into the use of "strategic treatment interruptions," that would allow people to miss doses.)
Two studies published in the journal Science, showed that although the virus lurked in the immune system of patients on triple combination therapy, it occupied very few cells, and even after two years of therapy had not developed resistance to the drugs. Dr. David Ho of the Aaron Diamond Center in New York said: "This news should be a motivation for patients to carry on and adhere closely to their regimen." These articles also reported that while HIV obtained from these people may not have been resistant after several years of treatment, the virus was still competent, that is, capable of causing widespread infection in the absence of effective drug therapy. These findings support the idea that treatment appears to need to be lifelong.
Steven Deeks, of the University of California, San Francisco, characterized drug failure as occurring most often in patients who have become drug resistant as a result of previous treatment or who have not adhered to dosage schedules. Deeks went on to explain that these studies "support the observation that in patients who have not taken antiviral drugs before and who take the combination as directed, 80 percent to 90 percent do well."
By early 1999, the overall euphoria -- as well as sensationalism and excessive optimism -- that followed the Vancouver conference had greatly diminished. "For many people, protease inhibitors are now 'old news'," said Alan Berkman, an HIV clinician in New York City, of the attitude among many patients by the end of 1998. "At first, there were all these dramatic examples of people rising from their deathbeds, but that was already a while ago. In the intervening time, people have seen that these medications are not a 'miracle cure,' and that they can be difficult to take. A lot of the skepticism about the medical system has returned among many patients, although there is still a recognition that antiretrovirals can help people with HIV stay well longer."
The mood identified by Berkman was reflected in the first post-Vancouver International AIDS Conference held in Geneva, Switzerland in July 1998. Where Vancouver displayed the revolutionary potential of the new treatment paradigm, the Geneva conference focused on small, incremental steps and careful analysis of existing data on combination therapies. Geneva covered a number of major themes, including the viral activity and mechanics of viral eradication, strengthening and rebuilding the immune system, drug resistance, new treatments, simpler drug regimens, strategies for using and adhering to antiviral drugs, longer-term side effects, and perinatal transmission. In almost every field, there was evidence that combination therapy continues to be effective over time, but that the drugs do not work for everyone, nor could anyone say how long the beneficial effect of treatment could be expected. Further a good deal of attention was paid to the problems of medication side effects and the challenge of adherence to demanding antiviral regimens.
The history of HIV treatments is a constantly unfolding one. Even as current therapies have demonstrated both enormous power and distinct limitations, new generations of treatments are in development.
Psychotherapist Michael Shernoff, M.S.W., and Body Positive Editor Raymond A. Smith, Ph.D. are co-authors of HIV Treatment: Mental Health Aspects of Antiviral Therapy (AIDS Health Project, University of California, San Francisco, 2000) from which this article was adapted.
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