This session is sponsored by the Center for Substance Abuse Treatment. CSAT Director Dr. H. Westley Clark addressed the group regarding concerns about discrimination against methadone patients in HIV studies and elsewhere. CSAT and FDA are working together to eliminate methadone patients exclusion from studies. CSAT is meeting with the transplant industry to discuss current discrimination preventing methadone patients from being listed as a potential liver transplant recipient.

Abstract

Persons with substance use disorders are at increased risk for a wide variety of medical complications. Preventive health practices that should be offered to drug users and models of care have been developed to provide comprehensive care. This session presents a medical update on Hepatitis C and HIV in drug users. As addiction psychiatrists, we are increasingly on the front line in terms of evaluation and initial identification of infectious diseases and other medical problems that our patients have. Using a case-based format, Dr. Stein discussed recent developments in HIV care relevant to addiction psychiatrists. Findings from the HIV Cost and Service Utilization Study (HCSUS) regarding the prevalence of psychiatric disorders in HIV-infected persons is addressed. Dr. O’Connor reviewed the epidemiology of Hepatitis C infection, the most common infection among drug injectors HCV disease course, and clinical markers used in determining treatment initiation decisions.

Symposium Chair: Edward V. Nunes, MD, Columbia University, New York State Psychiatric Institute, New York, NY

Evaluation and Treatment of HIV In Drug Users

Dr. Stein used a case study to demonstrate the importance of primary care evaluation for patients with HIV. This is a case of a 45-year-old woman who has received methadone for two months and who was referred to primary medical because of white plaques in her mouth and a sore throat. She was also seen for depression. She accepted HIV testing, and the white plaques in her mouth turned out to be thrush. She had the following lab work results—normal hemoglobin, HIV RNA (viral load of 43,000), T-cell count of 199, Hepatitis C positive with slightly elevated transaminases and a PPD that is 5mm. What do we do next?

We have a patient with a virus that turns over 1/3^rd daily—30 billion particles in the first few weeks, and two trillion lifelong. HIV is a rapidly replicating virus. Goals of treatment are to identify and treat non-HIV existing conditions. Those will include treating depression and HCV, controlling replication of HIV through medications if patient is willing, enhancing immune function which we now know some medications can do, and preventing the opportunistic infections (OI) of AIDS. This disease involves a declining T-cell count over time; you lose between 30 and 100 T-cells per year in the average population of people. Her T-cell count of 199 puts her in the range for risk of pneumocystis pneumonia. Some of the OIs such as CMV (cytomegalovirus) or MAC (mycobacterium avium complex) only occur with very low T-cell counts.

Most OIs that kill people occur when T-cell counts are less than 50, at least for those people receiving PCP prophylaxis. If we can take PCP out of the picture, as we have been doing for the past 15 years, with PCP prophylaxis using trimethoprim sulfamethoxazole, we know that the OIs that occur do occur late now. We know that the HIV RNA plays an independent role and confers the greatest OI risk for any iven CD-4 count if the HIV RNA is above 20,000. A high HIV RNA is an independent

predictor of disease progression. We used both numbers, the T-cell count andThe RNA, in order to guide treatment. Treatment guidelines have been a moving target for the past 10 years. Based on her T-cell count and RNA, we can look at HAART (Highly Active Antiretroviral Therapy). It is usually a three-drug combination. Most of these medication combinations are equipotent; they are also called drug cocktails. The choice of which drugs to use, at this point, is based on concomitant diseases such as diabetes, hyperlipidemia, hepatitis, and alcohol abuse that some of the medications will have interactions with.

The antiretrovirals form three classes: the nucleosie reverse transcriptase, inhibitors of which there are seven with Tenofovir being the latest and the only drug that was approved for this disease in 2001. There are three nonnucleoside reverse transcriptase inhibitors and there are the protease inhibitors of which there are now six. Many combinations across these 16 drugs can be created. Several more drugs should be approved in 2002.

What are the benefits and risks of delaying therapy? The guidelines are quite malleable on when to start and stop therapy. It is mainly the patient’s decision regarding readiness to take medication. The benefit of delaying therapy as long as possible to let the T-cell drop toward 200 is avoidance of the negative effects on quality of life. Also, drug resistance limits future options, which often results from poor patient adherence to the regime. Holding off using the first combination until as late as possible can save other combinations until the person is at greatest risk. However, there may be irreversible immune system depletion if the T-cell count goes too low and there may be greater difficulty in suppressing the viral replication as well as having an increased risk of transmission.

Short-term toxicities exist and they are nearly inevitable with the three-drug combination—nausea, headache, and hepatitis, including severe hepatitis called liver failure, diarrhea, or anemia. Long-term problems include lipodystrophy syndrome, also lipoatrophy, which is adding or subtracting body habitus. There are metabolic changes including insulin resistance, hypertrygliceridemia, hypercholesterolemia, and lacticacidosis, which can be fatal.

The interactions between methadone and HIV-related medications are relatively minor. There are several that are major that can cause methadone withdrawal. They include—nevarapine, also called VIramune or eFAVIRENZ which is called sustiva. Methadone does not cause significant clinical affects on any of the HIV medications.

Cohort studies suggest that viral load stability is good but transient increases are not so clinically meaningful; if you reach a viral load less than 50, the patient IS LIKELY to maintain this undetectable viral load for at least four years. Patients are monitored by checking HIV RNA and T-cell count as baseline sometime between the first and fourth week; if a person is adherent to medications, counts are repeated between two and six months. In monitoring visits for the blood work, we talk about adherence with patients. With greater than 95% adherence, there is less chance of virologic failure. With less adherence, the potential exists that the patient can lose future options for whole classes of drugs. This is an unforgiving disease; adherence to medications is critical. Patients generally overestimate their adherence. I believe patients who admit to nonadherence are more responsive to interventions and we plan to test this theory.

Adherence is promoted through patient preparation. The patient is given a talk about the pros and cons of therapy. The patient is asked to acknowledge that this requires a commitment and the patient has to believe it will work. We give instructions on side effects, whom to call, when to follow up, and information about their other medications. If there is a side effect from one of the three medications, we ask them to stop all three at the same time to reduce the risk of resistance. We discuss adherence tools such as times, calendars, who can help you, what do you do when you are away from home, and what is the social support system. Viral load feedback is provided at every visit when possible. When burnout on taking pills is anticipated, less intense dose regimens can be saved until later.

The HIV Cost and Service Utilization Study (HCSUS) is now appearing in the literature as a nationally representative sample of 3,000+ adults receiving HIV care in the United States in 1996. The sample consisted of people in care and excluded incarcerated people and people who just used ERs. There were significant percentages of psychiatric disorders in this group. In comparing the recent Household Survey with HCSUS, we found major depression in 36% of the HCSUS versus six percent for the Household Survey. Nearly half of the HCSUS sample had a psychiatric disorder. The Household Survey found 90% respondents with no drug use; HCSUS found 50% using drugs and alcohol.

Depressive symptoms go up at the time a patient is diagnosed and when they begin to have HIV-related symptoms. When the patient starts retroviral therapy, it becomes real to them, depression sets in, and sometimes there is an increase in substance use.

The HERS study of 765 HIV-positive women found a relationship between mortality, T-cell count and depressive symptoms. In the seven year follow-up study, the women with chronic depression were twice as likely to die during the follow-up period, controlling for the baseline T-cell count their viral loads, symptoms, retroviral use, age, drug use, and race. Chronic depression was associated with greater T-cell count decline.

Psychiatrists need to work with internists and share information such as neurocognitive deficit screening that doesn’t occur often in primary practice; this can affect adherence.

To facilitate adherence we need to maximize psychosocial functioning.

Evaluation and Treatment of Hepatitis C in Drug Users

Patrick O’Connor, MD, Yale University, Princeton, NJ

Based on 1999 CDC data, there are approximately 30,000 new cases per year of Hepatitis C in the United States. The seroprevalence of Hepatitis C virus (HCV) in this country is 1.8% in the general population. This translates into approximately four million Hepatitis C positive individuals in the United States. The main issue is chronic Hepatitis C infection. Of the individuals who are initially infected, about 85% will go on to develop chronic Hepatitis C—this is where we see the morbidity and mortality.

In a nationally representative sample of injection drug users in a 1996 study, the seroprevalence of Hepatitis C virus was 77% as compared to Hepatitis B which was 66%, HIV was 21%, and HTLV was two percent. The testing used in the early 1990s for Hepatitis C was less sensitive than currently available methods. In a Yale study of methadone patients using newer methods (second generation ELISA and RIBA), we tested 450 and found 435 were Hepatitis C positive—that is over 99%. Those few who were Hepatitis C negative in our study were generally people who just recently begun injecting.

Transmission is highly efficient among injection drug users in many areas across the country. Infection is rapidly acquired after initiation of drug injection behavior. Testing patients early is important so that serostatus can be known and appropriate action can be taken. Hepatitis C is also associated with intranasal cocaine use although the risk is considerably lower than the risk of infection from injection drug use. Other risk factors for HCV include:

1. blood transfusions before 1990,
2. organ transplantation,
3. occupational risks for health care workers including accidental needle sticks or during surgery; and
4. other lifestyle risk factors such as tattooing, extensive body piercing, and high risk sexual activities (i.e., multiple partners, a history of sexually transmitted diseases).

Because of the natural history of this disease, we generally miss identifying Hepatitis C. The incubation period after exposure to the virus is about six to seven weeks. Symptoms of acute infection develop only in about 25-35% of patients and most of those patients do not report for medical care or evaluation. These symptoms tend to be non-specific: fatigue and malaise. Jaundice is only present in 28-30% of individuals and can be very mild, going unnoticed. Thus the diagnosis of HCV is rarely established during the acute phase.

About 85% of the people who get infected acquire a persistent infection. A majority of these patients develop abnormal LFTs or more serious complications of chronic hepatitis. A minority remains clinically silent. This is very different from Hepatitis B where less than 10% of people get persistent infections. Chronic Hepatitis C became the leading cause of cirrhosis in the United States. It is responsible for 8,000 to 10,000 deaths per year. This number is expected to triple over the next 10-20 years. HCV has become the most common cause of liver transplantations in the United States.

Recommendations for routine Hepatitis C virus testing are based on risk for infection. High risk groups who should be routinely tested include: anyone who has every injected illegal drugs, those who received clotting factor or blood products before the late 1980’s, individuals on chronic dialysis, and those with persistently abnormal liver enzyme levels. Also, prior transfusion or transplant recipients from before 1992 should be tested.

Patients want to know the natural history of Hepatitis C. If you follow them over time you need to know what is going to happen with them. Hepatitis C is asymptommatic in the early stages. Diagnosis requires a high rate of suspicion of high risk behaviors in patients who are at risk for the disease. After the second decade with the disease, mortality and morbidity become much more aggressive and patients present with problems. The disease is not always progressive; when it does progress it can lead to cirrhosis, hepatic failure, and in some patients, hepatic carcinoma.

In a study examining trends in ALT (alanine transaminase) values in drug users, 43% had persistently elevated liver enzymes while 42% had persistently normal enzymes and 15% had intermittently elevated enzymes—sometimes normal and sometimes not. Risk factors for aggressive progression of HCV include an age of greater than 40, consumption of >50 grams of alcohol daily, and male gender.

Treatment of HCV includes the use of two medications: Interferon and Ribavirin. Interferon Alpha-2,B is typically administered in a dose of three million units weekly for six to 18 months. After six months of treatment, 50% of patients normalize or reduce their ALT by 50% or more; 50% of those who responded to therapy suffered a relapse within six months and about 20% have a sustained response with interferon alone. While most "outcome" data for treatment of HCV is based on the impact of treatment on serologic markers, we know less about the long-term clinical outcomes of treatment. This data is coming in, and the next few years should produce better information on the clinical (rather than the laboratory) impact of these treatments. Treatment over 12-18 months is generally more effective than six-month regimes that were initially looked at for using interferon. Better responses are found in younger patients, those not infected with viral genotype 1, those with low levels of viremia at pre-treatment, those with hystologically mind disease, and the absence of cirrhosis. Depression is a major concern as a side effect of Interferon. Severe life-threatening side effects are found in about two percent of patients.

Ribavirin is given by daily oral administration. It is usually very well tolerated and not effective when used alone; it is meant to

be used in combination with interferon. In one study, at the end of treament when Interferon/Ribavirin was compared with Interferon/Placebo, there was not much difference in terms of virologic response and biochemical response, During the followup time period after treatment, the patients receiving Interferon/Ribavirin tended to more likely have a sustained effect from the treatment..

The newest drug available to treat HCV is Pegylated Interferon—also referred to as Peg Interferon or Peg-I. It is manufactured by attaching polyethylene glycol to interferon. It is administered subcutaneously; its absorption is delayed in comparison to standard Interferon preparations. Therefore it has a longer half-life and can be administered once a week. This is a nice advantage for adherence. There are two Peg-I preparations, Alpha-2,a and Alpha-2,b. The relative efficacy of these two preparations is uncertain although generally considered both equally potent. Peg-I is on its way to becoming the standard of care approach for treating HCV given that it appears to be superior to older formulations of Interferon. Because of the drug’s long half-life, it needs to be used with great care or perhaps not used at all in patients with seizure disorders and those with severe depression.

Prevention strategies for patients who are HCV+ include abstinence from alcohol, and avoidance of any new medications without checking with the doctor (including over-the-counter medications, many of which include actominophen). Vaccination against Hepatitis A and B, if indicated, should also be provided. Close follow-up of liver function is very important. HCV+ patients cannot make blood or organ donations. Drug users who are HIV and Hepatitis C positive require a broad-based set of preventive health care measures. Vaccination against pneumococci infection is needed; and skin testing on an annual basis to look for TB is necessary. Screening for cervical cancer and STD is needed as well as vaccinations for diphtheria and tetanus.