TAG: The OI Report - research policy recommendations

THE OI REPORT:
A Critical Review of the Treatment & Prophylaxis of
AIDS-Related Opportunistic Infections (OIs)

RESEARCH & POLICY RECOMMENDATIONS
by Michael Marco, Theo Smart & Mark Harrington
General Principles of AIDS OI Research & Policy

The HHS Panel on Clinical Practice Guidelines for the Treatment of HIV Infection should commission a report on the treatment of AIDS-related opportunistic infections in order to complement the 1997 USPHS/IDSA OI prophylaxis guidelines.
Basic research on OI pathogens, particularly the less treatable ones, needs to be encouraged and expanded, in line with the recommendations of the AIDS Research Program Evaluation Working Group (the Levine Committee).
Drug discovery programs for anti-OI agents, such as the National Cooperative Drug Discovery Groups for OIs (NCDDG-OI), should be expanded, and innovative bench-to-clinic studies undertaken with particularly promising agents. NCI should expand its AIDS drug screen within the Developmental Therapeutics Program (DTP) to discover new anti-OI agents, as recommended by the Levine Committee.
Natural history studies should continue to measure the impact of potent protease inhibitor combination therapy (PPICT) on the incidence and prevalence of AIDS-related OIs at all CD4 levels, especially in patients who experience a significant rise in CD4 count from dangerously low levels.
Until randomized clinical trials prove that it is safe to discontinue PCP and MAC prophylaxis in patients whose CD4 counts increase above the threshold of risk while on PPICT, physicians should adhere to the USPHS/IDSA OI prophylaxis guidelines panel recommendation of "continuing prophylaxis based on the nadir of a patient's CD4 count."
Physicians should not take PCP, CMV or MAC patients on PPICT off their maintenance/suppressive OI therapy regimens until well designed clinical trials have proven that it is safe to do so.
The relationship between apparently complete suppression of viral load, CD4 rebound, immune reconstitution, cytokine activity, and replenishment of lost holes in the immunological repertoire should be rigorously assessed by collaborative clinical studies involving immunologists and infectious disease specialists.
Innovative approaches such as vaccinating HIV-infected persons with OI pathogen-derived antigens, with or without adjuvants such as cytokines which stimulate cell-mediated immunity, should be explored.
Clinical studies of OI induction and maintenance should gather prospective data about the relationship between treatment failure, drug interactions, drug absorption and metabolism, and the evolution of microbial drug resistance.
The impact of HIV load on risk and progression of OIs and the impact of OIs on mechanisms of HIV replication should continue to be studied. Herpes Simplex Viruses 1 and 2, Varicella Zoster Virus (HSV-1, HSV-2, VZV)
New drugs need to be developed against resistant herpesvirus strains.
The FDA should reconsider its rejection of sorivudine for VZV. Bristol-Myers Squibb should re-open planned studies for VZV retinitis and VZV encephalitis. Cytomegalovirus (CMV)
CMV PCR should be prospectively assessed as a prognostic marker for progression and response to therapy.
Routine ophthalmologic examinations should be a routine part of clinical management for patients with fewer than 100 CD4 cells.
Studies exploring the discontinuation of CMV maintenance therapy in patients on PPICT should not be conducted on those with detectable HIV RNA, detectable CMV DNA, or CD4 counts below 100.
Hoffmann-La Roche should expeditiously finish its first valganciclovir CMV retinitis treatment study and gear up for a new drug application to the FDA.
Hoffmann- La Roche should continue to work with and avail all necessary resources to the ACTG and SOCA for their planned valganciclovir pre-emptive therapy (targeted prophylaxis) study. Progressive Multifocal Leukoencephalopathy (PML)
We must become able to diagnose PML without conducting brain biopsies. Quantitative JC viral load assays for the blood and CSF need to be developed, and assessed for use in prognosis and treatment response. Mycobacterium Tuberculosis (MTB)
Tuberculosis thrives in poor socio-economic conditions, where nutrition is lacking, homelessness abounds and access to health care is not universal. Resources and commitment to combat these conditions are needed.
Since the risk of tuberculosis as an OI correlates strongly with the likelihood of a person's lack of access to health care, and because of the clear danger of non-treatment and non-adherence with treatment, public health programs to diagnose and treat tuberculosis must be continued and enhanced. Additionally, public health programs should be undertaken to train physicians and others in the diagnosis and treatment of TB. Other resources are needed to assure the availability of first and second-line TB drugs for all infected persons.
Directly observed therapy should be used when there is a risk of non-adherence, at a minimum. Integration of TB and HIV/AIDS services and effective communication between care providers should be encouraged.
Measures to identify and monitor MDR-resistant TB and to reduce nosocomial transmission of TB should be undertaken assiduously.
The development of effective short-course therapies for TB remains a priority.
The development of treatments for HIV and for TB that can be administered concomitantly is urgent.
Faster techniques for diagnosing TB infection (including in anergic persons) and assessing drug resistance are essential.
Shorter prophylaxis TB regimens and a vaccine suitable for use in immunocompromised patients would be truly welcome.
Significant improvements in TB management have taken place in the last ten years, and governmental support and funding must continue so that the mistakes made in the 1970s and 1980s do not occur again and undo the progress being made.
The three-way interaction among antiretrovirals, methadone and anti-mycobacterials needs increased attention from pharmaceutical sponsors and clinical research networks.
HIV patients on PPICT who develop tuberculosis requiring treatment with a rifamycin derivative should be maintained, whenever possible, on maximally suppressive antiretroviral therapy. If necessary, this may involve temporarily replacing one potent protease inhibitor with another. Mycobacterium Avium Complex (MAC)
MAC prophylaxis with a macrolide should be routinely given to persons with fewer than 50 CD4 cells, both to prevent MAC and for its additive protective effects against PCP.
Potent combination regimens which can eradicate MAC bacteremia are needed. Other Pathogenic Bacterial Infections
HIV-infected persons should be vaccinated for H. influenzae and Pneumococcus as early as possible after their HIV diagnosis.
The FDA should licence GCSF for the treatment of AIDS-related neutropenia and the prophylaxis of AIDS-related bacterial infections. Candida and Other Pathogenic Fungi
Well-controlled prospective comparative studies should be conducted of high-dose amphotericin B (liposomal versus standard) with or without flucytosine for induction treatment of endemic or rare disseminated fungal infections, and of high-dose fluconazole or itraconazole for maintenance.
Development of novel antifungal agents to treate azole-resistant pathogenic fungi remains an urgent priority. Cryptococcal Meningitis
Standard amphotericin B should be compared with liposomal forms of the drug in well-controlled studies, with or without flucytosine, to improve outcomes in the treatment of acute cryptococcal meningitis.
Guidelines for reducing elevated intracranial pressure (ICP) should be promulgated by an objective expert panel to make this intervention part of the standard of care for moderate to severe cryptococcal meningitis. Cryptosporidiosis & Microsporidiosis
Better in vitro and in vivo models for cryptosporidiosis and microsporidiosis are needed.
Considering the disappointing results of multiple monotherapy studies, perhaps combination studies of all partially-active agents should be considered. Pneumocystis Carinii Pneumonia (PCP)
Sponsors of TMP/SMX and Dapsone, along with the Public Health Service, should promulgate an aggressive campaign to encourage voluntary, anonymous HIV testing and CD4 screening to encourage people to discover their PCP risk status and start taking systemic PCP prophylaxis, if indicated.
Guidelines for desensitization or gradual initiation of TMP/SMX prophylaxis should be developed and broadly disseminated reflecting the latest clinical data.
Clinical trials exploring discontinuing PCP prophylaxis once CD4 counts rise above 200 while on PPICT should first be conducted on primary PCP prophylaxis patients. If proven safe, similar studies in secondary PCP prophylaxis patients should then be initiated. Toxoplasmosis
Screening for T. gondii antibodies should be a standard part of the baseline work-up for newly-diagnosed HIV-positive patients, and prophylaxis with TMP/SMX should be considered for those who are T gondii-antibody positive with CD4 counts below 200.
New, effective, less toxic treatment regimens are needed for treatment of toxoplasmosis.

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