Important note: Information in this article was accurate in April 1999. The state of the art may have changed since the publication date. | The online version of HEPP News displays the main article only, to view the entire newsletter download the following PDF:
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How many of the talks and posters presented at the 6th Conference on Retroviruses and Opportunistic Infections dealt directly with prisons? Very few! However, many of the presentations reported on new drugs and described new insights in the immunopathogenesis of HIV, both topics that are relevant to the management of HIV-infected patients in corrections.
The two predominant conference themes were "this is the era of drug resistance" and "improved T cell function due to HAART has not led to the eradication of the virus." Despite the lack of landmark changes in antiretroviral therapy, the good news is that for those who have access to them, current therapies continue to work.
Researchers from the University of Alabama opened the conference with a report on the origin of HIV-1. New evidence suggests that HIV is derived from human contact with chimpanzees in West Africa, who are infected with a strain of retrovirus similar to HIV. This presentation was the first to demonstrate homology in the virus from chimpanzees, geographic endemnicity and a plausible mechanism of transmission from animal to human through the chimpanzee meat trade.
Dr. Stefano Vella presented a discussion of "Antiretroviral Therapy in Adults," which focused on the emergence of resistance and salvage therapy. This reflected a growing concern among HIV providers about treating drug-resistant HIV. Dr. Vella reviewed retrospective studies of the genotyping and phenotyping assays that demonstrated the value of these new tools in the management of HIV resistance. Adding a cautionary note, he suggested that prospective clinical studies of genotyping and phenotyping will be required before we can determine whether clinicians can effectively use these tools to improve patient care. Notably, he warned against over-reliance on genotyping and phenotyping. This is because a viral provirus that is integrated into host DNA in latently infected cells may be a source of "archived" resistance to treatment, which may not be detected by these techniques (Vella, S. "Antiretroviral Therapy in Adults." 6th Conference on Retroviruses and Opportunistic Infections, Lecture 1, Session 2 Abstract L1.)
Others presented additional data on 153 patients who failed a protease containing regimen. They were randomized to management using either Genotypic Antiretroviral Resistance Testing (GART) or standard of care using routine clinical history. Patients randomized to GART were two-times more likely to become non-detectable than those whose management relied on routine clinical history (50% vs. 23% in the GART vs. Non-GART treatment arms). It appears that use of viral resistance testing will soon become part of standard clinical practice once standardization has been achieved. (Abstract LB8)
In other words, those of us providing clinical care to HIV-infected inmates will need to learn the proper use of these assays. GART will soon be part of the standard of care, however this will not supplant the need to elicit an accurate and detailed medication history from our patients. GART will complement our clinical history to optimize therapy for HIV-infected patients.
A number of speakers presented new approaches to HIV treatment that are in development. Fusion inhibitors are an exciting new product of basic research on the mechanics of HIV-1 fusion into T cells. Drugs that fall in this new class include chemokine receptor blockers and nucleocapsid inhibitors. One such drug, developed by Triangel Pharmaceuticals, is in phase I trials. In vitro studies of this drug were presented, showing that the new drug reduces the ability of the virus to infect new target cells (Abstract 616). Other similar drugs were presented in a session devoted to HIV treatment. This type of entry-blocking drug is unlikely to supplant current therapies, however it may be complementary once patients have been adequately suppressed using existing or new antiretrovirals.
One notable new concept was "single class triple therapy," also known as protease-sparing HAART. Three nucleoside reverse transcriptase inhibitors (NRTIs) are used instead of a protease - or non-nucleoside reverse transcriptase inhibitor (NNRTI) - inclusive regimen to treat HIV. This approach limits a patient's exposure to more than one class of HIV agents, thus reserving other agents for later (hence the term protease-sparing). A French group reported on the combination of D4T/DDI/3TC vs. D4T/DDI/Nevirapine and D4T/DDI/Indinavir. The regimens were essentially equivalent in patients with early HIV disease (Abstract 18). In another study, patients administered AZT/3TC/ABC suppressed their viral loads equally as well at 24 weeks as those on standard combination regimen, AZT/3TC/Indinavir (For more information on abacavir (ABC), see HIV 101.). The study's limitation is that insufficient data were available for patients with high viral loads, and until such are available, the use of ABC as part of a triple nucleoside analogue combination should be initiated with caution for those with high viral loads or more advanced HIV disease.
The conference also included interesting new pharmacokinetic data on the use of the combination of indinavir with ritonavir. The use of 100mg of ritonavir combined with 800mg of indinavir administered twice daily led to an excellent pharmacokinetic profile that was not affected by the administration of food. Current clinical studies will evaluate the efficacy of this combination versus ritonavir 400mg with indinavir 800mg in twice daily regimens. These dosing regimens are good news for corrections.
Safety and efficacy data were presented on two new protease inhibitors, amprenavir and ABT378 combined with RTV. Both had excellent safety and tolerability profiles (amprenavir is now available through compassionate use protocols). In a dosing study of ritonavir with ABT378 (in combination with D4T+3TC among antiretroviral naive patients), 93% achieved a VL<400 copies/mL among a group of patients with a mean baseline CD4 of 400 and VL of 100,000 copies/mL (Abstract 15).
Also highlighted was a potent, second generation protease inhibitor (AG1776), in development by Agouron Pharmaceuticals, that has excellent in vivo activity against many high level resistant strains of HIV with multiple mutations to existing protease inhibitors (Abstract 11). Agouron and DuPont Pharma presented data regarding three different second generation NNRTIs: DMP 961, DMP 963 (Abstract 13) and AG1549 (Abstract 12). These agents had excellent bioavailability and antiviral activity. HIV-1 isolates resistant to current NNRTIs were sensitive to these new agents. The number of mutations associated with the development of resistance was correlated with cross-resistance to these new agents. Again this supports the need to change treatment early when resistance is first detected.
Several speakers made reference to new HIV eradication time estimates. According to current estimates, based on our new understanding of latent reservoirs of HIV, the time it will take to eradicate HIV with HAART has increased from 18 months to 23 years. Clearly, more intensive approaches to treatment are required. Hope, however, should not be forsaken, provided these reassurances: 1) the total size of the HIV reservoir after HAART is thought to be small; 2) the latent reservoir may contain drug sensitive virus if treatment is initiated early and suppression of viral load is rapid; and 3) it is possible that additional decay in infection may become evident later with more potent antiretroviral regimens. Furthermore, new methods of activating and deleting latent virus using immunomodulators such as IL-2 demonstrate early success among patients with undetectable virus. Finally, as in the case of latent tuberculosis infection, elimination may not be totally necessary if immune control is adequate.
The relevance of these discussions to correctional HIV care are clear: we need to enable our patients to adapt to a lifetime of antiretroviral medication and select treatment regimens that are highly effective from the outset and that patients can adhere to. By meeting these goals, we will have patients who are living longer and are eligible for more aggressive therapeutic options in the future.
Adherence remains the cornerstone of effective antiretroviral therapy both for clinical trials and for clinical efficacy. It was demonstrated that adherence can be outstanding even among homeless patients. Much of the presented science described methods to measure adherence. While electronic devices were useful in monitoring adherence - although once thought to be the gold standard - they can be problematic. The bottom line is: develop effective ways for patients in corrections to have easy medication access and teach them effective mechanisms for taking pills. The pharmaceutical industry still has a long way to go in developing more user-friendly regimens for corrections.
Several abstracts presented data on the recovery of effective T lymphocyte responses among patients with advanced HIV who achieved virologic success using HAART. Although patients successfully responding to HAART may not always redevelop T lymphocyte responses to HIV, several studies demonstrated renewed responses to CMV, toxoplasmosis and MAC as well as other neo-antigens. Poor restoration of these responses was correlated with risk for relapse of opportunistic infections and/or new opportunistic infections (OI) among at-risk patients treated with HAART. These data suggest that for some patients, prophylaxis may be stopped, but we do not yet have access to the types of tools that would assist us with these difficult decisions (Abstract 453; Abstract 454; Abstract 455; Abstract 456; Abstract 457).
The timing of HAART initiation appeared to be a determinant of the recovery of responses to HIV antigens. Late treatment had some effect, but recovery of anti-HIV and anti-OI immune responses was less complete than among patients who were treated with effective antiretroviral therapy at earlier stages. More than one presenter made the analogy that "holes in the T cell repertoire" were more difficult to fill in with new, effective T cell responses the longer one delayed initiation of HAART (Abstract 329).
The case of the Berlin patient was presented in a poster (Abstract 351) along with a few other cases of "controlled HIV infection." Few adults, with the exception of this example have achieved complete viral suppression with the administration of HAART. The general consensus among participants was that the type of interrupted HAART combined with immune stimulation (due to acute Hepatitis A infection) that put the Berlin patient into apparent remission is not easy to replicate in other patients. Interrupted therapy will require intensive study before it can be determined that this approach will enable some patients to completely discontinue treatment. Patients who are interested in this approach should be referred to "centers of excellence." Those of us in corrections do not have enough data to support such an approach.
Looking toward the future of antiretroviral therapy, many speakers emphasized the need for new drugs with better resistance profiles and suggested that we initiate therapy with more potent regimens. Cost-intensive genotyping/phenotyping assays may need to be implemented more frequently as more patients fail their first and second lines of therapy. Studies demonstrating the prospective efficacy of these tools are needed.
HIV treatment is becoming more complicated with the emergence of resistance and the addition of new treatment regimens. The implication for corrections is that the management of HIV-infected individuals by experienced providers, and careful monitoring of patient adherence, is important if we want to pre-empt the need for greater reliance on cost-intensive assays.
Dr. Vella said in his closing remark that most of his recommendations addressed only 10% of the global population, and that the remaining 90% of people in the world who have no access to treatment should be considered. To place the problem of access to HIV care in a greater context, he quoted HIV expert Paul Volberding, who said "inequitable distribution of medical resources is not unique to HIV infection. Improving health care access is a challenge that extends beyond that of the HIV epidemic." Dr. Vella need not look much farther than the closest jail or prison. Parallels between health care access problems in the developing world and our patients' access to HIV care prior to incarceration are self-evident.
1999-0410
HEPP1999-0401
©1997,1998,1999,2000. The recently formed HIV Education Prison Project (HEPP) is a medical education program that targets a growing population, inmates in correctional facilities, that has been underserved in HIV care. It is part of the Brown University AIDS Program. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to heppnews@brown.edu. Website: HIV Education Prison Project.
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