On the same day as the opening of the 8th Annual Retrovirus Conference, the National Institutes of Allergy and Infectious Disease (NIAID, a division of the National Institutes of Health [NIH]) issued revised HIV treatment guidelines. The previous guidelines had advised that anti-HIV therapy should be considered, even when a person had no symptoms, if she or he had a T-cell count less than 500 or a viral load above 10,000 by bDNA or 20,000 by PCR.
A growing awareness of the long-terms side effects of anti-HIV therapy, the evident inability of current medications to eradicate HIV, and the better-than-expected immune recovery observed in people who begin therapy with T-cell counts between 500 and 350 have led to the latest change in the guidelines. The guidelines now suggest that therapy be considered when the T-cell count is below 350, or the viral load is above 30,000 by bDNA, or 55,000 by PCR.
At the Retrovirus conference, there were three presentations evaluating the impact of when anti-HIV therapy is begun. One presentation from the Swiss HIV Cohort purportedly showed a beneficial effect from initiating anti-HIV therapy when the T-cell count was above 350 (LB 6). However, this was a very poor study which retrospectively compared two very different groups of people: those who began therapy during a 1-year period when their T-cells were above 350, and those who did not start therapy during that year, the majority of whom (82%) never received therapy. Obviously, the first group had fewer adverse clinical events such as AIDS-defining illness and death. The more appropriate comparison group would have been people who started anti-HIV therapy after more than a year, with T-cells below 350, but before they got sick. There was an interesting observation in this study that of the people who started therapy, 60% changed at least one drug in their regimen (29% due to side effects), and 20% stopped therapy completely. These findings illustrate the problems of tolerance and adherence with the regimens used during the period of this study.
There were two other presentations (Abstracts 519 and 520), also retrospective cohort studies, that showed that there is a definite survival advantage for people to be on anti-HIV therapy if their T-cell count is below 200. The studies also showed a trend towards better clinical outcomes in people starting therapy with T-cell counts between 200 and 350, but no difference in people on or off therapy when their T-cells are above 350.
In the study presented by Timothy Sterling of Johns Hopkins University, it was observed that once CD4 cell count was allowed for, viral load did not predict clinical outcome. This study also showed that disease progression rates were worse in men, compared to women, in the group with fewer than 200 T-cells. Dr. Sterling concluded that more emphasis should be placed on the T-cell count in determining when to start therapy and that it appears that anti-HIV therapy can be deferred until the T-cell count is "substantially lower than 500" (Abstract 519).
The other study was from the CDC's Adult and Adolescent Spectrum of Disease Project, which includes data from over 5,000 people, from 11 cities in the United States, including Seattle (Abstract 520). They found that when anti-HIV therapy was deferred until after the T-cell count was below 200, there were more deaths. They also saw a trend, which did not reach statistical significance, for better outcomes in the group that started therapy when the T-cell count was between 200 and 350. There was no benefit observed for the group that began therapy with T-cell counts above 350.
The bulk of the findings from these studies provide support for the change in the HIV treatment guidelines, but each one also shows the limitations in data acquired from retrospective analysis.
At the Retrovirus press conference, STEP asked Dr. Fauci, Director of NIAID, if he was concerned that insurers and HMOs might try to deny coverage for people who choose to begin anti-HIV therapy, or continue on therapy, when they have T-cell counts above 350. He said that the guidelines panel tries to make its recommendations on the best available data. The panel is aware of the possible misuse of the guidelines, but the guidelines clearly state that the decision to begin anti-HIV medications is a complex one and must be made on an individual basis, in consultation between the patient and their healthcare provider.
Coincidentally, the week before Retrovirus, NIAID apparently decided that it is not feasible to conduct a large, prospective, randomized "when-to-start" trial in the United States at this time. Rather, the NIH will be investigating the feasibility of gathering data from observational cohorts. These groups of people will be followed closely, over a long period of time (5 or 10 years), and evaluated based on the when they initiated anti-HIV therapy, and any clinical events, such as opportunistic infections or medication side effects, that occur.
To read the press release from the NIH regarding the change in guidelines, go to http://www.niaid.nih.gov/newsroom/hivguidelines.htm.
People who began anti-HIV therapy with more than 350 T-cells and a viral load below 30,000 (bDNA), or 55,000 (PCR), may wonder how the new HIV treatment guidelines for when to start therapy apply to them. The decision of when to start anti-HIV medications, and subsequently when to stop them, remains very personal and is best addressed by an individual and their healthcare provider, using general recommendations as a guideline. For people who have had good suppression of HIV, with improvements in T-cells and minimal side effects, the risk of stopping therapy may outweigh the benefits. This is because almost everyone stopping anti-HIV medications has a very rapid rebound in viral load, and some people experience rapid losses in T-cells. So, the slowly gained benefits of anti-HIV therapy may be quickly lost. Additionally, there have been reports of people experiencing a primary-infection-like syndrome due to the rapid rise in viral load when medications are stopped. It is also important to emphasize that the revised guidelines attempted to balance the benefits of therapy against the potential long-term side effects. Long-term immune suppression due to untreated HIV also has consequences. One of the long-term effects of immune suppression is the risk of lymphoma, or cancer of the lymph nodes. In general, while the incidence in people with HIV has declined in the last few years, there are more reports appearing of people with higher T-cell counts being diagnosed with lymphoma. Thus, if someone is tolerating therapy and not experiencing significant side effects, it may be beneficial to continue the medications in order to keep the immune system as strong as possible. On the other hand, people who are experiencing significant side effects that can not be addressed by switching drugs, and who started therapy with relatively high T-cells counts and low viral loads, may decide to stop therapy, while still closely following their T-cell and viral load measurements.
See also "Ask Dr. Jeff," in this issue.
The makers of the new nucleotide analogue tenofovir have started offering the medication to people living with HIV through a limited early access program. Tenofovir is a compound that looks to be of use for people with resistance to currently available nucleoside analogue drugs. The early access program is designed to make the medication available to people who have run out of other viable treatment options. To be eligible to participate in the program a person must be at least 18 years old, have a CD4 count at or below 100, and an HIV RNA viral load greater than or equal to 10,000 copies. The program is also limited to those who have had treatment failure with at two protease inhibitors (PIs) or one PI and one non-nucleoside reverse transcriptase inhibitor (NNRTI). If a person has between 100 and 200 CD4 cells, and has had an AIDS-defining illness in the last 90 days, they may also be eligible. It is hoped that these criteria will be expanded to include more people as the drug gets closer to FDA approval (expected in June).
For more information about the tenofovir early access program in the U.S., call (877) 226-8802, or visit the website http://www.gilead.com/webpage_templates/frame_home.php3. To enroll patients in the program, U.S. physicians should call (800) GILEAD-5. Patients will receive the investigational drug as a once-daily, 300mg tablet.