"Fine Tuning" HIV Therapy
Report on the 9th Conference on Retroviruses and Opportunistic Infections
Clinicians and researchers met for the 9th annual Conference on Retroviruses and Opportunistic Infections in February in Seattle.
The conference -- one of the most important annual HIV-related meetings -- traditionally focuses on clinical management of HIV infection, as well as recent research on drug development, virology, immunology, epidemiology, and other topics. Of major interest this year were studies on the spread of HIV, starting and stopping therapy, oral sex and HIV transmission, new classes of drugs, co-infection with hepatitis C (HCV), and treatment complications.
Steady Incidence Rate
P.L. Fleming of the Centers for Disease Control and Prevention (CDC) and others reported that the HIV incidence in the United States remained steady at about 40,000 new cases in 2000, bringing the total estimated number of U.S. HIV cases to 850,000 to 950,000.
While HIV incidence has remained stable in the U.S., the percentage of newly diagnosed cases showing antiretroviral (ARV) resistance appears to be on the rise. Data from D. Bennett of the CDC and others showed that any-class ARV-associated mutations among recently diagnosed patients increased from 7.1 percent in 1999 to 10.7 percent in 2000, with mutations associated with protease inhibitors (PIs) accounting for most of the overall increase.
Another report presented at the conference concerned oral transmission of HIV. C. Celum of the University of Washington and colleagues evaluated throat-tissue samples from HIV-positive individuals to determine if they could culture HIV. They isolated HIV RNA in 24 percent of throat tissue samples from 17 patients, indicating that oral transmission of HIV is at least theoretically feasible. However, the study did not show whether oral transmission of HIV actually occurs.
As the use of resistance testing becomes more common in clinical practice, interpreting these tests can be difficult.
A study by N.T. Parkin of ViroLogic, Inc., and colleagues reported on the incidence of differences in phenotypic and genotypic test results. The study compared results from 200 blood samples tested with both phenotypic and genotypic tests and found that discordance was common. 75 percent of the samples tested were discordant for one drug, 54 percent for two drugs, 33 percent for three drugs and 22 percent for four drugs.
These results indicate that depending on which test is used, the choice of drug regimen could differ. The investigators suggested that the results of phenotypic testing may be better when reviewing discordant results since phenotypic testing provides a more quantitative assessment of resistance.
Stopping and Starting Therapy
Determining when to start and when to stop therapy was one of the major issues of the conference.
Two studies, the HIV Outpatient Study (HOPS) and data from T.R. Sterling of Johns Hopkins University and others, confirmed that initiating therapy at CD4 counts of greater than 350 cells did not provide a greater chance of treatment success or significantly delay the rate of disease progression. These findings substantiate last year's changes in the Department of Health and Human Services' HIV treatment guidelines, which recommend initiation of therapy at CD4 counts less than 350 cells. Furthermore, P. Hunt of the University of California at San Francisco and colleagues found that even patients who initiated therapy at very low CD4 cell counts had significant increases in CD4 cells over four years of highly active antiretroviral therapy.
Data presented on intermittent detectable HIV RNA -- also called viral "blips" -- indicated that the appearance of blips does not warrant a change in therapy. Retrospective data from two ACTG trials indicated that treatment failure was not predicted by viral blips. Although the cause of viral blips is still unclear it may reflect suboptimal viral suppression which is most commonly a result of lapses of adherence.
J.D. Lundgren and others of the EuroSIDA Study found that patients who stopped HAART had a greater mortality rate compared with patients who remained on therapy; however, the biggest factor in AIDS-defining events was CD4 count less than 200 cells, regardless of HAART status.
Structured treatment interruptions (STIs) were also investigated. The largest study to date, the Swiss-Spanish trial (SSITT), indicated that STIs are only beneficial for a minority of patients. The results suggest, though, that some patients may not need to be on any therapy. This is currently being investigated by other studies.
Cessation of therapy often occurs due to treatment fatigue, which is closely linked to treatment complications. M. Reiser and colleagues looked at predictors for serious adverse events among patients who had received 5 years of HAART. Among this large cohort, age, injecting drug use, low CD4 and prior AIDS were the most significant predictors for the development of a serious adverse event. Notably, the risk of death from a serious adverse event was comparable to the risk of death from disease progression. The data indicate that doctors and patients must be mindful of any potential therapy complications.
Cardiovascular Disease Link?
Several studies presented at the Retrovirus Conference attempted to investigate whether there is a connection between HAART and cardiovascular disease.
Mixed results were seen, with data from the HOPS and a large Dutch cohort indicating the use of PIs may increase the risk for cardiovascular disease. However, data from the Kaiser Permanente databank and S.A. Bozzette of the Veterans Administration Medical Center, San Diego, and others did not find a significant correlation between PI use and cardiovascular disease. It is hoped that future studies will clarify if HAART is associated with the development of cardiovascular disease.
Looking at Lipodystrophy
This year's conference also brought more data on lipodystrophy.
Despite the fact that the development of metabolic abnormalities and body shape changes among patients on HAART has been observed over a number of years, the scientific community has yet to come up with a satisfactory definition of the disorder. A. Carr of St. Vincent's Hospital and University of New South Wales and colleagues presented a model for diagnosing and following the development of body shape changes and metabolic abnormalities. This case definition may help standardize treatment of the disorder and allow for increased comparison of future lipodystrophy studies.
Fat Losses Examined
Carr and others also presented data on the treatment of lipoatrophy (the loss of fat in the extremities and the face). They found that patients with fat loss who switched from a thymidine analog (AZT or d4T) to abacavir (ABC) had a very slow reversal of limb, thigh and abdominal fat loss, although the changes were not visible. Those patients who remained on the thymidine analogs did not show any increase in fat loss, although the symptoms did not reverse.
J. Sutinen of Helsinki University Hospital and associates investigated whether the drug rosiglitazone, a medication used to treat insulin resistance, could be used to improve lipoatrophy in patients on HAART. This small study enrolled 30 patients and randomized them to either receive or not receive rosiglitazone. After 24 weeks, researchers found no change in body fat or subcutaneous fat. Although the results of this study were disappointing, further research is necessary to investigate if rosiglitazone has any potential to treat lipoatrophy and lipodystrophy.
It has been suggested that antiretroviral therapy may be associated with diminished bone mineral density which can lead to osteopenia and osteoporosis. Researchers at Washington University examined the connection between bone loss and antiretroviral therapy in a group of 128 patients.
They found low bone mineral density was predominantly related to factors other than antiretroviral therapy. Patients with low bone mineral density were more likely to have a history of weight loss or wasting, a history of steroid use or were current or past smokers.
Data on several new drugs were released.
Other drugs, such as integrase inhibitors and attachment inhibitors are also under investigation.
Hypersensitivity and Ziagen
Two interesting studies investigated whether the hypersensitivity reaction seen in 5 to 10 percent of individuals who take Ziagen can be predicted by a genetic test.
A recent report of a mother and son who both had Ziagen hypersensitivity reaction suggests it may have a genetic basis. The first study (abstract 91), conducted predominantly in a Caucasian population showed that 78 percent of individuals who developed the reaction shared a specific genetic marker (HLA-B 5701) and that only 2.3 percent of Ziagen-tolerant individuals had the genetic marker. In a second study, that included a more ethnically diverse population, identified the same genetic marker was present in 46 percent of individuals experiencing a reaction. The authors suggested that genetic tests may some day be used to reduce the risk of a hypersensitivity reaction in patients prescribed Ziagen.
Finally, promising news for patients co-infected with HIV and HCV was presented. Twenty-three patients who had HIV and had undergone either liver or kidney transplantation were reviewed. The majority of the transplantations were successful, even though the patients had to receive immunosuppressive therapy as part of the transplantation process. For co-infected patients, treatment for HCV has continued to improve, with patients receiving pegylated interferon alpha and ribavirin showing sustained virologic response against HCV.
Researchers at the Hospital Pitie-Salpetriere in Paris undertook a study to determine if biochemical markers (blood tests) could accurately predict fiborsis without the need for a liver biopsy in patients with chronic hepatitis C infection. The researchers looked at a five-marker panel of tests that included: total bilirubin, gamma glutamyl-transpeptidase, alpha-2 macroglobulin, apolipoprotein A1, and haptoglobin. The most useful markers in the analysis were alpha-2 macroglobulin, apolipoprotien A1, and patient age at the time of biopsy. The researchers estimated that the use of the five-panel test could have removed the need for a biopsy in 55 percent (72) of the patients at a cost of eight wrong diagnosis. Accuracy was 89 percent.
For more information on the conference, visit www.retroconference.org.
David Pieribone assisted in reviewing this article. An "HIV Matters" presentation by Mark Katz, M.D. on March 12 was used in research.
Back to the April/May 2002 issue of Positive Living.
This article was provided by AIDS Project Los Angeles. It is a part of the publication Positive Living.