DOCTOR FAX

ISSUE 10 1st November 1997

Sourced Compiled and Edited by Paul Blanchard
Medical Advisor - Dr Graeme Moyle, Chelsea & Westminster Hospital.

CDC Issues Warning to Physicians on Protease Inhibitor Interactions
Agouron To Submit New Drug Application For HIV Protease Inhibitor Nelfinavir
"Hospitals Keep Drug Packs in Case of AIDS Accidents"
HIV-1 Activated Following Blood Transfusion
Can HIV-1 Transmission be Prevented During Pregnancy and Labour?
"HIV Perinatal Transmission Risk Not Affected by Infection Outcome of Previous Siblings"

Viral Load Testing - Specimen Collection and Storage

DRUG INTERACTIONS

CDC Issues Warning to Physicians on Protease Inhibitor Interactions

The Centers for Disease Control (CDC) in the US published warnings to physicians on October 25th concerning the concurrent use of HIV protease inhibitors and drugs commonly used to treat TB.

Reproduced below is the full text of the warning published in the Morbidity and Mortality Weekly Report.

MORBIDITY AND MORTALITY WEEKLY REPORT

Centers for Disease Control and Prevention
October 25, 1996
Vol. 45/No. 42

Clinical Update: Impact of HIV Protease Inhibitors on the Treatment of HIV-Infected Tuberculosis Patients with Rifampin

In 1995 and 1996, the Food and Drug Administration (FDA) approved three products in the new protease inhibitor class of drugs - saquinavir (Invirase TM ), ritonavir (Norvir TM ), and indinavir (Crixivan TM ). Another drug in this class of agents, nelfinavir (Viracept TM ) (Agouron Pharmaceuticals), is expected to be available soon from the manufacturer through an expanded-access program. All four drugs, which inhibit HIV protease and thus interfere with viral maturation and replication, are the most potent antiretroviral agents available to treat patients with HIV disease (1). However, these protease inhibitors interact with rifamycin derivatives, such as rifampin and rifabutin, which are used to treat and prevent the mycobacterial infections commonly observed in HIV-infected patients. Rifamycins accelerate the metabolism of protease inhibitors (through induction of hepatic P450 cytochrome oxidases), resulting in subtherapeutic levels of the protease inhibitors. In addition, protease inhibitors retard the metabolism of rifamycins, resulting in increased serum levels of rifamycins and the likelihood of increased drug toxicity (2). This report describes approaches for managing patients who are candidates for or who are undergoing protease inhibitor therapy when tuberculosis (TB) is diagnosed and presents interim recommendations for managing these patients until additional data are available and formal guidelines are issued.

BACKGROUND

Rifampin is an essential component of the currently recommended regimen for treating TB (3). This regimen is efficacious in treating HIV-infected patients with TB and consists of isoniazid and rifampin for a minimum of 6 months, plus pyrazinamide and either ethambutol or streptomycin for the first 2 months (4,5). Therefore, the pharmacokinetic interactions between protease inhibitors and rifampin are important for health-care workers involved in TB control and the care of patients co-infected with TB and HIV because clinicians may decrease or restrict the use of rifampin in the treatment of patients who are candidates for therapy with both protease inhibitors and rifampin. Prompt initiation of appropriate drug therapy for patients with HIV infection who acquire TB is critical because TB may be rapidly fatal (6). Drug therapy is a critical personal health measure for curing TB and minimises the impact of this disease on the progression of HIV infection; in addition, drug therapy is a major public health measure for interrupting the transmission of Mycobacterium tuberculosis to persons in the community.

Currently, the manufacturers product labelling for protease inhibitors contraindicates, does not recommend, or discourages the concurrent administration of rifampin and protease inhibitors. Because of the common association of TB and HIV infection, an increasing number of patients probably will be considered candidates for rifampin and protease inhibitors. The management of these patients is complex, requires an individualised approach, and should be undertaken only by or in consultation with an expert. In addition, all HIV-infected patients at risk for TB infection should be carefully evaluated and administered isoniazid for preventive treatment if indicated, regardless of their status for being prescribed protease inhibitor therapy.

MANAGEMENT OPTIONS

TB Management for Patients for Whom Protease Inhibitor Therapy Is Being Considered but Has Not Yet Been Initiated

For HIV-infected patients diagnosed with drug-susceptible TB and for whom protease inhibitor therapy is being considered but has not been initiated, the suggested management strategy is to complete TB treatment with a regimen containing rifampin before starting therapy with a protease inhibitor. The duration of this anti-TB regimen is at least 6 months, and therapy should be administered following current guidelines published by the American Thoracic Society and CDC (3), including the recommendation to carefully assess clinical and bacteriologic response in patients co-infected with HIV and to prolong treatment if response is slow or suboptimal. Antiretroviral agents other than protease inhibitors may be used concurrently with this regimen. Directly observed therapy (DOT) is routinely recommended for the treatment of TB to ensure adherence with the recommended regimen and is available through local health department TB-control programs. Among patients who adhere to therapy, four-drug regimens are expected to be effective even in those infected with strains of M. tuberculosis resistant to isoniazid or streptomycin alone. However, the management of patients with drug-resistant TB should be evaluated on a case-by-case basis and individualised based on the results of drug-susceptibility studies.

TB Management Options for Patients Undergoing Protease Inhibitor Therapy

There are three options for managing HIV-infected patients with TB who are undergoing protease inhibitor therapy when TB is diagnosed. One option is to discontinue therapy with the protease inhibitor while undergoing a TB treatment regimen that includes rifampin. However, because of the potential that interruptions in the administration of the prescribed protease inhibitor can induce HIV resistance to the protease inhibitor and possibly to other drugs within the protease inhibitor class (1) and because discontinuation of protease inhibitor therapy may be associated with a detrimental effect on the patients clinical status, some clinicians may be reluctant to discontinue protease inhibitor therapy for the duration of TB treatment. In such cases, two additional options may be considered. Because the risks and benefits of all these options are unknown, clinicians should individualise management decisions on a case-by-case basis to provide optimal patient care.

Option I. This option involves discontinuing therapy with the protease inhibitor and completing a short (minimum 6 months) course of TB treatment with a regimen containing rifampin. This anti-TB regimen should be administered following current guidelines published by the American Thoracic Society and CDC (3), and the duration of therapy should be prolonged in patients with slow or suboptimal responses. Protease inhibitor therapy may be resumed when treatment with rifampin is discontinued. Antiretroviral agents other than protease inhibitors may be used concurrently with rifampin. Although the risks associated with a complete discontinuation of protease inhibitor therapy while undergoing TB treatment are unclear, they may be serious; however, the risks and complications associated with TB treatment regimens that do not include rifampin are known. Potential consequences include prolonged duration of therapy to at least 18-24 months, increased likelihood of treatment failure and mortality (7, 8), slower conversion of sputum culture to negative with patients remaining infectious for longer periods of time, and the adverse effect of TB disease on the progression of HIV infection (9,10). Therefore, nonrifampin-containing regimens are not recommended for the treatment of rifampin-susceptible TB.

Option II. To minimise the interruption of protease inhibitor therapy, one option is to use a four-drug TB treatment regimen that includes rifampin (i.e., daily isoniazid, pyrazinamide, rifampin, and ethambutol or streptomycin) for a minimum of 2 months and until bacteriologic response is achieved (i.e., sputum conversion to culture-negative status), and the results from susceptibility testing are available. After bacteriologic response and drug susceptibility have been documented (usually 3 months), treatment may be modified to a 16-month continuation-phase regimen consisting of isoniazid (15 mg/kg) and ethambutol (50 mg/kg) two times per week. This regimen allows the reintroduction of protease inhibitor therapy. Some experts consulted for this report recommended adding a third drug, such as streptomycin, during this continuation phase if the infecting organism is not resistant to the drug. Option II cannot be recommended for patients with proven isoniazid-resistant TB.

Option III. The other management option is to continue protease inhibitor therapy with indinavir (800 mg every 8 hours) and administer a four-drug, 9-month TB-treatment regimen containing daily rifabutin (150 mg/day) instead of rifampin. When this option is used for TB management, clinicians should conduct careful monitoring, possibly including measuring serum concentrations of rifabutin - a service available only in specialised centers in the United States. This alternative TB therapy is recommended based on the pharmacokinetic characteristics of rifabutin and limited data from clinical trials. Rifabutin is a rifamycin derivative with comparable anti-TB activity in vitro but with less hepatic P450 cytochromic enzyme-inducing effect than rifampin (11, 12). An international multicenter study indicated that a 6-month regimen containing rifabutin, at the daily dose of either 150 mg or 300 mg, was as effective for treating TB as a similar regimen containing rifampin (13). In a small clinical trial, a rifabutin-containing regimen was effective in treating TB in patients co-infected with HIV (14). In addition, limited data from pharmacokinetic studies suggest that the combination of rifabutin at 150 mg/day and indinavir resulted in acceptable levels of both drugs (15). Option III cannot be recommended for patients undergoing therapy with ritonavir or saquinavir. For these patients, the decision to change the prescribed protease inhibitor to indinavir and to prescribe rifabutin for TB therapy should be made in consultation with an expert in the use of protease inhibitor to manage HIV infection. In the United States, rifabutin is approved by FDA for the prevention of disease caused by M. avium complex (MAC) but not for the treatment or prevention of TB.

ADDITIONAL RECOMMENDATIONS

Neither option II nor option III have been studied in large clinical trials of HIV-infected patients or patients undergoing protease inhibitor therapy during TB treatment. For these reasons, if either of these options are selected for managing patients with TB, CDC recommends the following interim guidelines until additional data are available and formal guidelines are issued: 1) on initiation of therapy, perform frequent bacteriologic evaluations to document sputum conversion to culture-negative status, and after culture conversion, to detect any possible treatment failures, 2) extend the duration of therapy to at least 18 months for option II or 9 months for option III, 3) use only indinavir with option III, 4) carefully monitor for drug toxicity, 5) use DOT throughout, and 6) re-evaluate periodically during the first 2 years after completion of therapy (including an assessment of bacteriologic status at six months) and instruct patients to promptly report symptoms compatible with relapse of TB disease. The management of HIV-infected patients diagnosed with drug-resistant TB or diagnosed clinically with TB but without culture and susceptibility-testing results should be evaluated on a case-by-case basis and performed in consultation with a TB expert.

CONCLUSIONS

In the future, concurrent use of protease inhibitors with rifampin might be possible by modifying the doses of both to compensate for the drug interaction. For example, based on limited data submitted to FDA during the new drug application review for ritonavir, a slight increase in the dosage of ritonavir and a reduction by half in the dosage of rifampin may have resulted in satisfactory levels of both drugs. However, this option cannot be recommended until data from larger, more detailed studies are available and will require careful monitoring of the serum levels of rifampin.

Interactions between protease inhibitors and the rifamycins also have complicated prophylaxis and treatment for disseminated MAC disease. Rifabutin is one of the drugs recommended for MAC prophylaxis ( 16 ). According to the manufacturer of indinavir, rifabutin at half the dose (150 mg) can be used for MAC prophylaxis simultaneously with indinavir. Other options for MAC prophylaxis are clarithromycin and azithromycin ( 17,18 ), two macrolide antibiotics approved by FDA for this purpose and for which interactions with protease inhibitors are expected to be less of an issue. In November 1996, a joint working group of the Public Health Service and Infectious Disease Society of America will update recommendations for MAC prophylaxis.
To reduce the likelihood of drug interactions while providing optimal anti-TB care for HIV-infected persons, health-care workers involved in the care of patients with TB and health-care workers involved in HIV clinical care are encouraged to co-ordinate efforts and thus ensure the best possible outcome for these patients. CDCs Research and Evaluation Branch, Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, (telephone [404) 639-8123]) requests the inclusion of clinical information in the comments section of TB surveillance reports from private practitioners or health department staff who manage HIV-infected patients undergoing protease inhibitor therapy when TB is diagnosed.

Reported by: Center for Drug Evaluation and Research, Food and Drug Administration. Div of Tuberculosis Elimination, and Div of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, CDC.

References
1. Bartlett JG. Protease inhibitors for HIV infection. Ann Int Med 1996;124:1086-8.
2. Sun E, Heath-Chiozzi M, Cameron DW, et al. Concurrent ritonavir and rifabutin increase risk of rifabutin-associated adverse event [Abstract no. B.171]. Presented at XI International Conference on AIDS. Vancouver, July 8, 1996.
3. Bass JB Jr, Farer LS, Hopewell PC, et al. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994;149:1359-74.
4. Small PM, Schecter GF, Goodman PC, Sande MA, Chaisson RE, Hopewell PC. Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med 1991;324:289-94.
5. Perriens JH, St Louis ME, Mukadi YB, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire: a controlled trial of treatment for either 6 or 12 months. N Engl J Med 1995;332:779-84.
6. Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993;329:784-91.
7. Perriens JH, Colebunders RL, Karahunga C, et al. Increased mortality and tuberculosis treatment failure rate among human immunodeficiency virus (HIV) seropositive compared with HIV seronegative patients with pulmonary tuberculosis treated with standard chemotherapy in Kinshasa, Zaire. Am Rev Respir Dis 1991;144:750-5.
8. Okwera A, Whalen C, Byekwaso F, et al. Randomised trial of thiacetazone and rifampicin-containing regimens for pulmonary tuberculosis in HIV-infected Ugandans. Lancet 1994;344:1323-8. 9. Whalen C, Horsburgh CR, Hom D, Lahart C, Simberkoff M, Ellner J. Accelerated course of human immunodeficiency virus infection after tuberculosis. Am J Respir Crit Care Med 1995;151:129-35.
10. Wallis RS, Helfand MS, Whalen C, et al. Immune activation, allergic drug toxicity, and mortality in HIV-positive tuberculosis. Tubercle Lung Dis (in press).
11. Kunin CM. Antimicrobial activity of rifabutin. Clin Infect Dis 1996;22(suppl 1):S3-S14.
12. Blaschke TF, Skinner MH. The clinical pharmacokinetics of rifabutin. Clin Infect Dis 1996;22(suppl 1):S15-S22.
13. McGregor M, Olliaro P, Wolmarans L, et al. Efficacy and safety of rifabutin in patients with newly-diagnosed pulmonary tuberculosis. Am J Respir Crit Care Med (in press).
14. Schwander S, Rusch-Gerdes S, Mateega A, et al. A pilot study of antituberculosis combinations comparing rifabutin with rifampicin in the treatment of HIV-1 associated tuberculosis.
Tubercle Lung Dis 1995;76:210-8.
15. The Indinavir (MK 639) Pharmacokinetic Study Group. Indinavir (MK 639) drug interaction studies. Presented at the XI International Conference on AIDS. Vancouver, July 8, 1996. 16. USPHS/IDSA Prevention of Opportunistic Infections Working Group. USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: a summary. MMWR 1995;44(no. RR-8):1-34.
17. Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex (MAC) infection in patients with advanced acquired immunodeficiency syndrome. N Engl J Med 1996;335:384-91.
18. Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996;335:392-8.

All three protease inhibitors now licensed for marketing in Europe and expanded access for nelfinavir planned. Rifampin is known as rifampicin in the UK, it is an approved anti-mycobacterial drug that is a standard component in combination regimens for the treatment of TB. Rifabutin is approved in the UK for the prophylaxis of MAI in people with CD4 counts below 100. Discontinuation of the protease inhibitor along the lines of Option 1 above and substitution with a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) for the duration of the TB treatment may provide sufficient antiviral cover. Unfortunately there is no access to NNRTIs in the UK outside of placebo controlled trials. Despite Nevirapine being approved in the US, Boerhringer Ingelheim has still not allowed access to the drug in the UK either through named patient or open label clinical trials. Pharmacia Upjohns NNRTI delarvirdine should be available through open label clinical trials but has been held up for months in hospital ethics committees proving that this route of providing expanded access in the UK is not acceptable

Options for MAI prophylaxis other than rifabutin include clarithromycin daily or once weekly azithromycin (1250mg). Whilst clarithromycin is contraindicated with ritonavir, it increases saquinavir levels and does not affect levels of indinavir.

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ANTIVIRALS

Agouron To Submit New Drug Application For HIV Protease Inhibitor Nelfinavir

Agouron Pharmaceuticals, Inc., has announced that it will proceed promptly to assemble and file with the U.S. Food and Drug Administration (FDA) a New Drug Application (NDA) seeking approval to commence marketing of the company's HIV protease inhibitor nelfinavir mesylate (Viracept TM). The company's decision was based upon an analysis of initial results from three pivotal clinical trials of nelfinavir. Agouron said that submission of the NDA for nelfinavir should be completed not later than in the first quarter of calendar 1997.

ATP understand that Agouron will be pursuing application with the European Medicines Evaluation Agency (EMEA) in parallel with their FDA application. It will be interesting to observe this parallel track and whether drug will appear in US and European pharmacies simultaneously. Phase III studies of nelfinavir are planned for Europe including a study looking at the combination of nelfinavir and saquinavir and Agouron are still looking for potential sites for these trials - interested centres should contact Agouron or ATP. An expanded access programme for nelfinavir in Europe is expected to begin in January 97 with a minimum expected 600 doses consideration but details of access criteria are still being debated between the company and treatment activists.

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"Hospitals Keep Drug Packs in Case of AIDS Accidents"

Hospitals in Toronto are starting to prepare for the accidental exposure of health-care workers to HIV by keeping drugs to treat such exposures on hand. The plan is based on recommendations made by the U.S. Centers for Disease Control and Prevention in July, which call for treating HIV-exposed workers with a combination of antiviral drugs that includes a protease inhibitor. Studies in the United States have found that immediate treatment can reduce a worker's risk of developing AIDS by 70 percent. The CDC recommends that the drugs, which cost about $1,200 per person, are used only in very high-risk cases, like a deep prick from a needle that has been used on an AIDS patient. The agency said the level of risk should be balanced against the effects of the drug. The government of British Colombia has stocked every emergency room in the province with five-day starter packs of the drugs, to be available for anyone accidentally exposed to HIV.

Source: Toronto Globe and Mail (10/17/96) P. A7; Coutts, Jane

The Expert Advisory Group on AIDS is expected to issue guidelines shortly on post-exposure prophylaxis (PEP) including non-health care worker exposure such as condom breaks. Whilst AZT has shown benefit this is unlikely to be optimum due to the slow onset of action of nucleoside analogues (due to intracellular phosphorylation). NNRTIs and protease inhibitors which are given as the active compound should be considered for inclusion in a PEP regimen. Therapy should also be individualised based on the source of exposures drug experience and the likelihood of resistant virus.

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PATHOGENESIS

HIV-1 Activated Following Blood Transfusion

"The transfusion of blood to persons with advanced HIV-1 infection modestly increases plasma levels of HIV-1," according to a team of researchers lead by Dr. Michael M. Lederman of Case Western Reserve University in Cleveland.

Dr. Lederman evaluated plasma viral load in nine patients with AIDS before and after they received blood transfusions for refractory anaemia. He found "...a modest rise in plasma HIV-1 p24 antigen and plasma HIV-1 RNA beginning 1 to 2 weeks after the blood transfusion." For all subjects, the mean change in plasma p24 antigen was 9.3 pg per mL two weeks after transfusion, and 18 pg per mL after four weeks. Compared with baseline, plasma HIV-1 RNA levels rose by a mean of 84% at one week, 70% at two weeks and 67% at four weeks after transfusion.

"This preliminary report indicates that transfusion is temporally associated with an increase in plasma virus load," Dr. Lederman writes, adding that the underlying mechanism responsible for the increase in plasma HIV-1 is unknown. "Although these rises are modest, plasma levels of HIV-1 vary only minimally over a 4-week period in otherwise stable, HIV-1-infected patients." However, he also points out that the significance of these findings is unclear.

Ref: Transfusion 1996;36:860-865.

Transfusion is now much less common due to availability of non-haematotoxic antiretrovirals and lower doses of AZT. Transient rises in viral load due to infections, vaccinations and transfusions are not currently considered a major concern as viral load usually falls to pre-event levels within 4-6 weeks. Adequate antiviral cover with triple combination therapy would be expected to prevent these transient rises in viral load.

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OBSTETRICS

Can HIV-1 Transmission be Prevented During Pregnancy and Labour?

Caregivers have little control over the majority of the factors that increase the risk of mother-to-infant HIV transmission during pregnancy and delivery, according to French researchers. Laurent Mandelbrot and colleagues analyzed the pregnancy and delivery history, and the HIV-1 status at 18 months, of more than 1,600 children born to HIV-1 infected mothers. The study preceded the introduction of zidovudine use for the prevention of mother-to-child transmission, some 19 percent of the infants were found to be seropositive at 18 months. Factors that the researchers identified as increasing the risk of transmission included: invasive procedures, such as amniocentesis and amnioscopy; sexually transmitted diseases during pregnancy; preterm delivery; premature membrane rupture; haemorrhage during labour; and blood in the amniotic fluid. Except for the use of invasive procedures, caregivers have little control over these factors, the researchers said. Moreover, factors that the caregiver could control--such as protracted labour and skin abrasions--were found to have little influence on transmission. The researchers recommend that invasive procedures be avoided during pregnancy and that vaginal infections be quickly diagnosed and treated.

Ref: Lancet (10/12/96) Vol. 348, No. 9033, P. 1021

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"HIV Perinatal Transmission Risk Not Affected by Infection Outcome of Previous Siblings"

The risk that a woman will transmit HIV to a child does not increase with time, according to researchers at Emory University. In the Paediatric Infectious Diseases Journal, Dr. Steven Nesheim and colleagues report on a study of 114 HIV-positive women who gave birth to at least two children after becoming infected. Among members of that group, 18 percent of the younger siblings and 17 percent of the older children became infected. The researchers concluded that strong maternal factors do not affect the risk of perinatal transmission, but rather that the risk is linked to factors associated with the individual pregnancy and delivery.

Source: Reuters (22/10/96)

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VIRAL LOAD TESTING

Specimen Collection and Storage

Blood should be collected in sterile tubes using EDTA (lavendar top, Becton Dickinson #6454 or equivalent) or ACD (yellow top, Becton Dickinson #4606 or equivalent) as the anticoagulant.

Specimens anticoagulated with heparin are unsuitable for this testing.

Store whole blood at 2 - 250C for no longer than 6 hours.

Separate plasma from whole blood within 6 hours of collection by centrifugation at 800 - 1600g for 20 minutes at room temperature.

Transfer to a sterile polypropylene tube. (It is recommended that specimens be stored in 225 - 250 L aliquots in sterile, 2mL polypropylene screw cap tubes (such as Sarstedt catalog no. 782.694.006).

Plasma Storage

Plasma specimens to be stored at room temperature for up to 1 day; at 2-80C for up to 5 days, or frozen at -200C to -800C. Plasma specimens may be frozen and thawed up to 3 times.

Specimen Transport

Transportation of whole blood or plasma must comply with all country, federal, state and local regulations for the transport of ethiologic agents. Whole blood must be transported at 2-250C and processed within 6 hours of collection.

Plasma may be transported at 2-80C or frozen.

Guidelines provided by Roche Diagnostics but also apply to samples collected for Chirons b-DNA assay

The next issue of AIDS Treatment Projects Doctor Fax will include an article by Dr Graeme Moyle on Treatment Sequencing as part of our Current Opinions series.

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