amfAR, The Foundation for AIDS Research

Landscape Shifts for Both Prevention and Treatment

A Report From the 13th Conference on Retroviruses and Opportunistic Infections

By Rowena Johnston, Ph.D.

March 1, 2006—If there’s one constant in HIV research, it’s that seemingly self-evident truths are always changing. Some of the research presented at this year’s Conference on Retroviruses and Opportunistic Infections, held February 5-8 in Denver, drove home this point.

When should HIV therapy be started?

Prevailing wisdom says that the later a patient starts taking anti-HIV therapy, the fewer the likely side effects and toxicities. After all, the total amount of time spent on therapy, and thus the total doses of drugs taken, will be less. However, Dr. Kenneth Lichtenstein of the University of Colorado Health Sciences Center has turned that assumption on its head. He and his colleagues conducted a retrospective study of the medical records of 2,304 patients and found that those who began treatment early, when CD4+ T-cell levels were at 350, were 60 percent less likely to develop kidney failure, 30 percent less likely to develop peripheral neuropathy (a painful condition in the nerves of the extremities), and 60 percent less likely to develop lipoatrophy (a loss and/or redistribution of body fat), compared with patients who started therapy late, when their CD4+ T-cell count was less than 200.

It is important to note that current guidelines for initiating treatment have not changed, however. These guidelines recommend that patients whose CD4+ T cells have fallen below 350 should consider starting therapy, while those with counts lower than 200 should definitely begin treatment. While Dr. Lichtenstein’s findings appear to place these guidelines in some doubt, experts are quick to point out that this is only one study, which has not even been published yet. Moreover, it may be difficult ever to answer the question of exactly when therapy should be started because such clinical trials take so long that by the time they’re finished, new drugs and recommendations may well be in place.

How SMART is it to stop therapy once you’ve started?

Stopping therapy once it has been initiated is strongly discouraged, yet in the context of a few clinical trials, doctors are investigating safe ways patients might be able to take so-called “drug holidays.” Doctors continue to tweak guidelines for when to start therapy, but it's unclear if it might ever be possible to take a break from medication. The questions are closely related, for in both instances researchers are looking into ways that patients can minimize the number of drug doses they take. Again, the theory goes that any time spent off therapy would reduce the chance of side effects or toxicities.

One huge clinical trial known as SMART (Strategies for the Management of Antiretroviral Therapy) tracked the clinical course of 5,472 patients. One group of patients continued to take therapy as usual, while the other varied medication according to CD4+ T-cell count. Therapy was discontinued if participants’ T cells rose above 350 and resumed if they fell below 250. Dr. Wafaa El-Sadr, an amfAR Program Board member, presented the results, which indicated that, on every measure, patients in the group that discontinued therapy fared worse than those who continued to take all their drug doses. Serious disease progression among these patients was more than six times greater than the control group, and their death rate was no less than two and a half times higher. These numbers could not express more powerfully that stopping and resuming therapy, at least using these guidelines, is not a “smart” option.

A new drug class—Integrase inhibitors

One of the big stories of the conference was the description of two integrase inhibitors, one produced by Merck (MK-0518) and the other by Gilead (GS 9137). HIV contains three enzymes—integrase, reverse transcriptase, and protease—but until now drugs have only been available to counteract the activities of the latter two. Inhibitors that block the activity of integrase have been slow in coming, largely due to toxicity issues.

The good news is that both companies have come up with compounds that appear to be safe and effective, both at reducing levels of virus in the blood (viral load) and, in the case of the Merck compound, increasing patients’ CD4+ T cells. Both drugs can reduce viral load by up to two logs (e.g., from 50,000 to 500), which is impressive for any new anti-HIV drug. While the news looks good so far, both drugs are in phase II clinical trials, meaning that they are at least several years away from FDA approval and wide availability to patients.

Benefits of circumcision cut both ways

Last year at the International AIDS Society Conference in Rio de Janeiro, the story that made the biggest splash was undoubtedly the news that circumcision can reduce a male’s risk of acquiring HIV by up to 75 percent. Those results came from a study of 3,520 18-24 year-old men in South Africa who were initially uncircumcised. This year in Denver, Dr. Thomas Quinn of the National Institutes of Health added to the good news when he reported that the female partners of HIV-positive circumcised men are less likely to acquire the virus than women whose HIV-positive partners are not circumcised. A woman’s risk of acquiring sexually transmitted infection is also lower for herpes, human papilloma virus (often linked to cervical cancer), trichomonas, bacterial vaginosis, and genital ulcer disease. Interestingly, though, male circumcision offers no protective effect for women against syphilis, chlamydia, or gonorrhea.

The result of circumcision is some of the best news the HIV field has received in a long time. And as prevention interventions go, it is relatively inexpensive. A single circumcision performed under sterile conditions by a medical practitioner costs $69, while the cost of averting one new HIV infection by using nevirapine to reduce mother-to-infant transmission is around $2,500. Of course, a condom costs still less, but it can only work when people are willing to use it.

 

25 years of HIV/AIDS: Lessons learned

As head of the CDC’s Sexually Transmitted Disease Control Division when AIDS was first identified, conference keynote speaker Dr. James Curran has been actively engaged in the fight against HIV/AIDS for two and a half decades. Dr. Curran described six key lessons that have been learned over the last 25 years, lessons that continue to guide amfAR’s programs and activities.

1. “Good surveillance is the conscience and the compass of the epidemic.” The nature of the HIV/AIDS epidemic continues to change, and in order to target prevention and care resources optimally, we need to be aware of and responsive to those changes.

2. “AIDS is not like other diseases….Biological and social factors favor its insidious spread and long-term persistence.” HIV is highly stigmatizing, it preferentially affects the poor, and women are particularly vulnerable because of their relatively powerless status in most societies.

3. “Innovative science can overcome skepticism.” In the early years of the epidemic, many were dubious that the cause of AIDS would ever be discovered—“so if the skeptics were wrong before, how about those who are skeptical about an effective HIV vaccine or HIV curative therapy today?”

4. “HIV prevention works.” While great effort is directed towards treating the infected, effective prevention interventions exist and they need to be scaled up.

5. “HIV prevention is not as simple as ABC [abstinence, be faithful, use condoms, the method promulgated by the U.S. administration]—it is far too important and far too complicated to be alphabetized….The politics of HIV prevention are international and national, while prevention itself is individual, interpersonal, and community based.”

6. “People make the difference—those who have HIV, caregivers, scientists, and other concerned leaders.”

Dr. Johnston is director of research at amfAR.