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International AIDS Conference: Compliance issues Studies show long-term adherence to antiretroviral equals long-term efficacy

Susman, Ed

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Even though political activism tends to be the hallmark of the International AIDS Conferences, the 2004 biennial meeting in Bangkok – the best attended meeting in the history of the conclave – was notable for studies which described tong-term adherence to highly active antiretroviral therapy (HAART).

A striking study found that even highly experienced patients who had reached the end of the road with oral HAART were able to benefit from injectable enfurvitide, the first of the fusion inhibitors.

Calvin Cohen, MD, medical director of Harvard Vanguard Medical Associates, Boston, Massachusetts, USA, reported that not only were patients able to sustain twice-daily subcutaneous injections with enfurvitide, but the results of maintaining that treatment had a beneficial impact on viral load.

`‘After two years, twice as many patients have achieved virological success than people on their optimal regimes,’’ said Dr. Cohen, one of the myriad investigators involved in the long-running T-20 versus Optimized Regimen Only (TORO) studies.

Contrary to clinician and patient belief, the need for twice-daily injections is not seen as a major problem once the patients starts using the drug and becomes aware if its benefits. ‘‘The patients taking enfurvitide find it much easier to inject themselves than do most people who haven't tried it,’’ he said.

In fact, Dr. Cohen said that he was somewhat frustrated by surveys that indicated four of ten doctors did not even mention enfurvitide to their patients who were candidates for the drug because of the perceived notion that the patients wouldn't take the shots. He also noted, that three of six patients offered enfurvitide turn it down due to needle phobia or other reasons. ‘‘A perceived fear of needles drives about 90% of the decision to reject use of Fuzeon,’’ he said.

In reviewing the TORO data, Dr. Cohen said that after 2 years 26% of patients on enfurvitide – once known as T-20 and marketed as Fuzeon by Roche of Nutley, New Jersey, USA, and Trimeris of Durham, North Carolina, USA – had undetectable virus loads compared to 13% of patients who were taking the most effective background antiretroviral therapy. The original study compared outcomes of patients on best optimal background therapy versus those taking enfurvitide in addition to the background therapy [1].

Five years of lopinavir

The first time that researchers heard of clinical tests with the combination of lopinavir/ritonavir was when they attended the 1998 International AIDS Conference in Geneva. Study 720 continues to be reported at almost every HIV/AIDS and infectious disease meeting, and now, after 5 years, researchers report that resistance to the protease inhibitor remains rare. No patient in the study developed resistance to the lopinavir/ritonavir protease inhibitor, said Charles Hicks, MD, associate professor of medicine at the Duke University Medical Center, Durham, North Carolina, USA. ‘‘Even in people whose virus came back, there doesn't appear to be any resistance. That suggests it might be possible to use this treatment over relatively long periods of time,’’ he said.

To determine whether HIV developed resistance to the drugs, Hicks analyzed more than 5 years of data from 100 patients participating in Study 720, a randomized, blinded, multi-center trial of lopinavir/ritonavir. Since the start of the study, the dual protease inhibitor product has been approved by the US Food and Drug Administration. The drug is marketed as Kaletra by Abbott Laboratories, Abbott Park, Illinois, USA. Abbott funded the study.

After 252 weeks of follow-up, 64% of the patients in Study 720 had undetectable levels of HIV in their blood. A total of 27 patients had experienced low-level viral rebound during the 5-year period, i.e., the virus rose to detectable amounts in their blood. Samples for genetic testing of HIV drug resistance were available from 17 of those patients.

The researchers found none of the 17 patients had HIV with resistance to lopinavir. Nor did the virus develop resistance to stavudine. Resistance to the final component of the regimen, lamivudine, was also uncommon [2].

Long-term effectiveness

In another study, researchers said that HAART based on the protease inhibitor fosamprenavir allowed HIV patients to maintain undetectable viral for at least 2 years.

`‘Long-term treatment with GW433908/ritonavir (now marketed as Lexiva by GlaxoSmithKline) resulted in sustained virological suppression, continued immunological improvements and no new safety concerns over 96 weeks,’’ said Joseph Gathe Jr., MD, director of Therapeutic Concepts, Houston, Texas, USA.

Dr. Gathe reported of 115 of 210 patients who had completed 2 years of therapy. About 96% of the patients in the extended trial had achieved an undetectable viral load, using the 400-copy/ml assay, Dr. Gathe said. Using the 50-copy/ml assay, about 86% of patients had undetectable circulating virus, he said. The average CD4-positive cell count increased 263 × 106cells/l after 96 weeks [3].

Once-daily saquinavir

A once-daily, hard-gel formulation of saquinavir, as the protease inhibitor component of HAART successfully suppresses HIV. ‘‘The regimen of saquinavir in the hard-gel capsule given in combination with stavudine and didanosine showed excellent efficacy over 24 weeks,’’ said Jintanat Ananworanich, MD, a lead researcher with the HIV Netherlands Australia Thailand (HIVNAT) Research Collaboration, Bangkok.

Dr. Ananworanich said that after 24 weeks of treatment with the combination therapy 90% of patients achieved an undetectable viral load using the stringent 50-copy/ml assay. More than 95% of patients suppressed their viral load to below 400 copies/ml.

In addition, the average CD4-positive cell count increased by 100 × 106 cells/l among the 167 patients in the trial which was supported by Roche. Both the reduction of viral load from baseline and the increase in CD4-positive cells from baseline reached statistical significance at the P < 0.001 level, she said [4].

Trial experience replicated in ‘‘real world’'

What works well in clinical trials doesn't necessary do so well in the real world in treating patients with HIV, but researchers who looked at outcomes in two diverse clinics found that tenofovir when added to a HAART package was effective in reducing viral loads—often to undetectable levels.

`‘Tenofovir disoproxil fumarate was widely and successfully used in both clinics in various scenarios,’’ said James Scott, Pharm.D., Western University of Health Sciences, Pomona, California. ‘‘It has become a widely used agent in the treatment of HIV, due to its efficacy, tolerability and convenient dosing. In the study we conducted, patients were started on tenofovir, a nucleotide reverse transcriptase inhibitor, for a variety of reasons but most commonly due to adverse events of other nucleoside reverse transcriptase inhibitors, especially thymidine analogs, and prior treatment failure.’'

The researchers looked over the records of patients from two clinics: The Jeffrey Goodman Special Care Clinic in Hollywood, California, USA, that cares for more than 2000 HIV-infected patients who are mostly uninsured and most often are men who have sex with men; and the Pacific Oaks Medical Group, a private practice clinic in Beverly Hills, California, which has mostly insured patients who most often are men who have sex with men.

There was little difference between patients at the two centers in adherence or efficacy [5].

Drug holidays possible

While doctors constantly preach that patients have to be compliant with their HAART regimens, the life-long bill burden takes its effect psychologically and financially.

Dr. Cohen attempted a ‘‘drug holiday’’ approach during which patients would take their medicine every workday, but would keep their pills in the medicine cabinet on weekends.

`‘We have been able to show in this pilot program that patients can take their medication for 5 days and then stop taking the medication for 2 days – or over the weekend – and maintain virologic control,’’ said Dr. Cohen, who is also director of research for the Community Research Initiative of New England, Boston, Massachusetts, USA.

Dr. Cohen recruited 23 men for the year-long study—one of several structured treatment interruption trials that have been attempted during among patients with HIV infection who have maintained undetectable viral loads. ‘‘In our study, the participants had to have their viral loads below the 50-copy detection level for at least 3 months before entering the trial,’’ Dr. Cohen said.

While most of the men chose to take medicine Monday through Friday, a few had different days off work and therefore timed their schedules with work. In the FOTO (5 days on, 2 days off) study, patients were on a variety of regimens. Those who were taking non-nucleoside reverse transcriptase based regimens with efavirenz or with nevirapine as the backbone drug showed consistent ability to keep the virus suppressed below the level of quantification throughout the study. However, patients taking a protease inhibitor based regimen exhibited some viral rebound that was detected in standard tests. ‘‘Those patients were immediately put back on a 7-day regimen,’’ Dr. Cohen said. ‘‘They were subsequently able to return to undetectable viral loads without changing medication.’'

`‘The study,’’ said Anthony Fauci, MD, director of the US National Institute on Allergy and Infectious Diseases, ‘‘shows similar results to what we have seen over the years—that short term holidays in drug treatment seems safe and reduces the amount of drugs people need to take. I think it is a good thing’’ [6].

Websites

HIV Netherlands Australia Thailand (HIVNAT) Research Collaboration, Bangkok

www.hivnat.org

Harvard Vanguard Medical Associates

http://www.harvardvanguard.org/

Kaletra

www.kaletra.com

GSK Worldwide

www.gsk.com/

Ed Susman

References

1. Arastéh K, Lazarin A, Clotet B, Lalezari J, Cooper D, Henry K, et al. TORO: 96 week virological and immunological response and safety evaluation of enfuvirtide with an optimized background regimen.XV International AIDS Conference. Bangkok, July 2004 [abstract MoOrB1058].
2. Hicks C, Da Silvam B, Benson, C, Wolfe, P, Gulick, R, Glesby, M. Extensive resistance testing during 5 years of lopinavir/ritonavir treatment in antiretroviral-naive HIV infected patients: Results from study m97-720.XV International AIDS Conference. Bangkok, July 2004 [abstract WeOrB1291].
3. Gathe J, Wood R, Bellos N, Stark T, Elston R, Millard J, et al. Long-term follow-up on GW433908/ritonavir (908/r) QD: sustained virologic and immunologic response in antiretroviral treatment naïve subjects over 96 weeks.XV International AIDS Conference. Bangkok, July 2004 [abstract TuPeB4507].
4. Ananworanich J, Ruxrungtham K, Siangphoe U, Chetchotisakd P, Prasithsirkul W, Kiertibursnakul S, et al. A prospective cohort study of efficacy and safety of 2 NRTIs plus once-daily ritonavir boosted-saquinavir hard gel capsule (SQV-HGC/r) at 24 weeks.XV International AIDS Conference. Bangkok, July 2004 [abstract TuPeB4469].
5. Scott JD, Wolke PR, Quiros J, Behrooznia E, Guyer B, Bolan KR. Retrospective review of the use of Tenofovir DF in 2 clinical practices.XV International AIDS Conference. Bangkok, July 2004 [abstract TuPeB4633].
6. Cohen CJ, Morris A, Bazner S, Gordon D, Sheble-Hall S, Narayan R, et al. The FOTO Study: A pilot study of short-cycle treatment interruption, taking antiretroviral medications for five days on, two days off (FOTO), for those with viral load suppression on either PI or EFV-based regimens.XV International AIDS Conference. Bangkok, July 2004 [abstract TuPeB4575].
© 2004 Lippincott Williams & Wilkins, Inc.