A broad overview is provided of three critical areas in this article: provision of highly active antiretroviral therapy (HAART), treating opportunistic infections, and emerging treatment developments. Adherence, management of side effects, and cost of care, all of which are impacting the promise and limits of current therapies, are also highlighted.

Guidelines for the Use of Antiretroviral Agents for HIV-Infected Adults and Adolescents

Last updated in May 1999, Guidelines for the Use of Antiretroviral Agents for HIV-Infected Adults and Adolescents was developed by the Panel on Clinical Practices for Treatment of HIV Infection. The U.S. Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the panel.

Initiating Therapy

The Guidelines indicate that the decision to initiate or modify antiretroviral therapy should be based on the HIV RNA viral level, the CD4+ cell count, the clinical condition of the patient, and the preference of the patient.  Viral load should be measured every 3 to 4 months after infection and CD4+ cell count should be tested every 3 to 6 months.  All symptomatic HIV-infected people who have progressed to AIDS should be treated with antiretroviral therapy.  In an asymptomatic1  patient there may be a benefit in initiating therapy before symptoms appear. 

In considering whether to start treatment, the physician and patient must balance the potential for control of viral replication and maintenance of a functioning immune system against the possibility of reduced quality of life from adverse drug effects, possible earlier drug resistance, and limitations in the future choices of antiretroviral agents that result from resistance.

Treatment goals

Once the decision to initiate therapy is made, the goal of treatment should be maximal suppression of HIV to undetectable levels.  Initial treatment should consist of two nucleoside reverse transcriptase inhibitors and one 
potent protease inhibitor, though evidence also appears to support the use of efavirenz, a non-nucleoside reverse transcriptase inhibitor in place of the protease inhibitor.  In addition, the patient's viral load should be tested from 2 to 8 weeks following the initiation or modification of antiretroviral therapy; if the drugs are effective and are being used as prescribed, the viral load should become undetectable with 12 to 18 weeks of therapy. 

Ensuring Success

To ensure success, the clinician, treatment team, and patient must collaboratively select a treatment regimen.  Issues of patients' social and economic supports, their preparedness to follow the regimen, and their ability to access the therapy must be assessed and addressed.  Physicians, nurses, social workers, pharmacists, and treatment and peer advocates can work with patients to consider their readiness to begin treatment and to provide support to patients once treatment is begun.  Assessing adherence to treatment is complex. Laboratory indicators, memscaps, pillboxes, pill counts, and thorough patient interviews are some of the tools that may be used.  See Table 1: Strategies to Improve Adherence.

When to Switch

A detectable viral load, a persistently declining CD4+ cell count, or a declining clinical condition suggests treatment failure, and consideration of a new antiretroviral regimen should ensue.  The decision to change failing therapy and the choice of new therapy should be based on the patient's clinical condition, the CD4+ cell count and viral load, viral resistance patterns, the remaining treatment options and their side effects, and the patient's expected adherence to a new combination of drugs.²

Side Affects

In addition to the identified adverse effects of antiretroviral agents (See table IX in the guidelines), several metabolic-related conditions have been observed in many patients.  These side effects primarily include insulin resistance, hyperlipidemia, and fat redistribution—generally subcutaneous fat depletion and visceral fat accumulation.  Hepatic steatosis and lactic acidosis, both serious and sometimes fatal conditions, also have been observed.

The etiology, incidence, and long-term consequences of these complications are not fully understood.  Some may be associated with specific drugs or with classes of drugs.  There also may be gender-based differences in their effects.  There is no universally agreed upon definition, making identification and tracking difficult, but as many as 60 percent of patients may be affected.  Many believe the cause of these negative consequences to be multi-factorial, and may include a patient's own medical and family history, antiretroviral agents, and duration of treatment. 

Clinical management of these conditions may include changing—not stopping—the HAART regimen.  Management techniques also may include assessment of a patient's cardiac risk factors, additional laboratory testing (e.g., lipid panel, glucose testing), and body composition analysis, counseling on diet and exercise, and medication to counter hyperglycemia and/or hyperlipidemia.  Other treatments, such as use of hormones and anabolic steroids, use of nutritional supplements, liposuction and plastic surgery, also are used to counter some of these effects.

These conditions clearly further complicate antiretroviral treatment decisions. As more is known about these possible side effects, clinicians must continue to educate patients and strive to understand the possible impact on adherence to therapy.  In addition, new supports and services may be needed to address these conditions (e.g., greater access to testing, increased patient education and support, access to pharmacologic agents, and access to specialists).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection was last updated in April 1999.   
Included are antiretroviral treatment recommendations for HIV-infected infants, children, and adolescents.  The Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, convened by the National Pediatric and Family HIV Resource Center, the Health Resources and Services Administration, and the National Institutes of Health, developed these guidelines.

Principles in Pediatric HIV/AIDS Treatment

Since identification and treatment of HIV-infected pregnant women has a significant benefit in terms of reducing transmission to their offspring and in caring for those who are HIV infected, the guidelines recommend that all pregnant women in the United States be counseled and tested for HIV with their consent during pregnancy.  A multidisciplinary team including physicians, nurses, social workers, psychologists, nutritionists, outreach workers, and pharmacists should care for children with HIV and their families. The guidelines also urge that antiretroviral drug clinical trials be opened to children and that pharmaceutical companies manufacture drug formulations appropriate for them.

Pathogenesis of HIV Infection in Children

The pathogenesis of HIV infection in young children is different in some essential respects from that in adults.  Generally, the disease is acquired perinatally, usually soon before or during childbirth.  Therefore, it is possible to treat the patient at the same time the infection takes place.  In addition, because the child's immune system is incomplete when it is infected, clinical disease and immunological and viral markers differ from those of adults. Finally, drug pharmacokinetics change from the neonatal to adult period so drug dosing and toxicity must be considered separately from that of adults.

Diagnosis of HIV in Infants

The evaluation of infants born to HIV-infected mothers is complex.  They should start AZT at birth and be tested for the HIV virus by 48 hours and again at 1 to 2 months and finally at 3 to 6 months. Two positive tests are necessary to diagnose HIV infection. HIV infection can be ruled out if there are two negative tests, one at greater than 1 month of age and the second at 4 months or greater.

Initiating HAART in Infants

HIV-infected asymptomatic infants less than 1 year old are at increased risk of disease progression so therapy should be initiated as soon as confirmed diagnosis is established; however, the guidelines indicate that clinical trial data demonstrating this approach are currently not available and that information on drug dosing in neonates is limited.

Children and infants with clinical symptoms of HIV or evidence of decreased immunological function should be started on antiretroviral therapy regardless of viral load.  For asymptomatic children greater than 1 year old, the guidelines outline two approaches: treat, or defer treatment and monitor virologic, immunologic, and clinical status closely.  While there have been relatively few clinical trials in children, the guidelines borrow from studies on adults and recommend combination therapy with two nucleoside reverse transcriptase inhibitors and one potent protease inhibitor or efavirenz in place of the protease inhibitor. As with adults, any child on antiretroviral therapy must be closely monitored for changes in immune, virologic, or clinical status.

Adherence Among Infants and Children

As with adults, an assessment of a child's ability to adhere  must be conducted when planning a treatment regimen.  Social and economic supports must be considered. Whether the child can tolerate the medication and swallow pills is clearly crucial. The family's understanding and beliefs regarding the illness; issues of disclosure to other family members, caregivers, school and day care providers; and the family's schedule and caregiver's availability should be completely assessed by the treatment team. Families should continue to receive education and support throughout treatment, and the treatment team should continuously monitor adherence and respond to barriers as they are identified.³

Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus

The guidelines for treating opportunistic infections were last updated in August 1999 by the U.S. Public Health Service and the Infectious Disease Society of America (IDSA).  Nineteen specific opportunistic infections are considered in these guidelines with recommendations for prevention of exposure, prevention of disease and prevention of recurrence (see table 2).  In addition, the guidelines discuss when primary prophylaxis may be halted to the extent such information is available.  For example, there is evidence that primary prophylaxis of pneumocystis carinii pneumonia may be discontinued when a regimen containing a protease inhibitor has caused a sustained increase in CD4+ cells to above 200.  Similarly, the guidelines find that it is reasonable to stop primary prophylaxis against Mycobacterium Avium Complex when there is a sustained increase in CD4+ cells to above 100.  The guidelines discuss both how to avoid contact with infectious agents and medications that prevent the associated diseases when they are available.  There is attention to special populations such as children and pregnant women.

Outpatient costs have risen in recent years due to the costs of HAART, but a falling number of hospitalizations and shorter average length of hospital stay have resulted in lower inpatient costs.

The cost of treating a person with HIV infection is dependent, in part, on the person's stage of disease.  One recent study found that estimated 1 year costs of care were lowest for persons with the lowest viral load and highest CD4 counts. Conversely, it was most expensive for persons with highest viral loads and lowest CD4 counts.  The median cumulative 1 year costs for all patients were $22,716, while the median for the healthier group was $15,632, and for those with more advanced disease, $24,708.

A Medicaid annual cost of care model estimates that the annual cost of care for persons with HIV enrolled in Medicaid ranges from $6,792 to $73,500 depending on stage of disease.  The model indicates that increases in expenditures for antiretroviral therapy lead to decreases in other health care costs and that "moving patients from sub-optimal antiretroviral therapy to HAART may be cost effective."⁵  

However, in one study presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy in September 1999, overall costs rose after an initial decrease associated with HAART.  The reasons cited were cost of medications and unspecified non-HIV clinic outpatient visits; "these data warrant followup to determine their accuracy and, if confirmed, their causes."⁶

There is evidence that routine use of costly genotype testing (described below) does not increase the cost of care, because its expense is offset by decreased cost of antiretroviral therapies since clinicians are better able to select medications that will be effective.  Also, patients with genotype management had a greater drop in viral load than those managed with viral load, CD4 counts, and antiretroviral history alone.⁷  

While more study is needed to determine their optimal role in the clinical management of HIV, there are several circumstances in which viral resistance testing may be useful.  For example, prior to selecting initial therapy in newly-infected patients, especially in geographic areas with a high rate of primary infection with resistant strains of HIV, it may be beneficial to conduct such tests.  In addition, resistance testing may help in selecting a new drug regimen in a treatment-experienced patient when salvage therapy is warranted.  Clinical trials are being conducted to determine if viral resistance testing has the potential to improve the clinical outcome for patients with HIV.

Some of these new drugs in existing and new classes currently are available under early access and compassionate use programs while still in clinical trials.

Nucleotide analogs will be the next class of drugs available; tenofovir, which offers once-daily dosing and a new alternative for treating patients in which resistance has developed, will be at the forefront.  Fusion inhibitors, designed to prevent the virus from entering uninfected cells in the body, will likely soon follow.  Adult and pediatric clinical trials of two fusion inhibitors, T-20 and T-1249, both of which are given subcutaneously, are currently underway.  Other fusion inhibitors also are being studied.

Additional classes of drugs under investigation include integrase inhibitors and nucleocapsid zinc finger inhibitors.  If successfully developed, they may offer additional points of attack on the virus and be particularly useful in treating people infected with strains of HIV that are resistant to current drug classes.

"Like the treatment with most chronic diseases, antiretroviral regimens are complex, have major side effects, pose difficulty with compliance, and carry serious potential consequences with the risk of resistance from non-adherence to the drug regimen or sub-optimal levels of antiretroviral agents.  Patient education and involvement in therapeutic decisions is important for all medical conditions, but is considered especially critical for HIV infection and its treatment."

In addition, clinicians should establish consultative and referral relationships with HIV specialists and with other sub-specialists in order to make better treatment decisions and increase their knowledge base for providing care.

Except when planning treatment for HIV-exposed newborns, pregnant women or patients with identified acute HIV infection,⁸  clinicians and patients have the time to weigh carefully the risks and benefits of treatment.  Assessing the factors influencing adherence and effectiveness of the chosen agents can maximize the success of a treatment regimen. 

HIV-positive Individuals in Care are Poorer than the General Population

Data from the HIV Cost and Services Utilization Study (HCSUS), a nationally representative sample of HIV-positive adults receiving medical care in the contiguous United States, show that individuals living with HIV disease are poorer than the U.S. population at large. 

"As compared with others in the non-elderly population, adult patients with HIV were about one-half as likely . . . to be employed, to have a household income above the 25th percentile, or to have private insurance."¹

HCSUS researchers interviewed 2,864 HIV-positive individuals between January 1996 and March 1997.  Sixty-five percent of the survey respondents named a CARE Act-funded medical provider as their usual source of care.

CARE Act Clients Poorer than Other HIV-positive Individuals in Care

As compared to HIV-positive individuals served by clinics without CARE Act support, the clients of CARE Act-funded providers were more likely to report annual household incomes of $10,000 or less in 1995 (55 percent vs. 34 percent), Medicaid coverage (34 percent vs. 24 percent), or no health insurance (28 percent vs. 6 percent).  They also were more likely to be black (43 percent vs. 20 percent) and female (26 percent vs. 18 percent).  Thirty-nine percent of the clients seen at CARE Act-funded clinics had not completed high school, as compared to only 19 percent of the clients seen at other clinics.

Client Demonstration Project Data

Three additional studies of clients receiving services at CARE Act-funded sites corroborate the HCSUS findings.  HRSA's HIV/AIDS Bureau funds five metropolitan areas (Los Angeles, San Francisco, and Orange County CA, Washington DC, and Middlesex County NJ) and two States (Michigan and Virginia) to collect data on the characteristics and service use of individual clients across networks of CARE Act-funded providers.  In 1998, the 303 providers participating in this Client Demonstration Project served 44,874 clients. Eighty percent of service users had annual incomes less than 300 percent of Federal Poverty Level, and 39 percent were uninsured.  Almost two-thirds of the clients (62 percent) were people of color.  Women accounted for 21 percent of all clients served.

New Clients at Title III Sites in 1997

During 1997, 200 clinics funded by Title III of the CARE Act provided primary health care, oral health services, nutritional counseling, case management, and support services to 25,746 new clients.  Forty-three percent of these clients had no health insurance.  Of the 22,797 clients for whom income data were available, 90 percent had incomes at or below 300 percent of Federal Poverty Level.

SPNS

The CARE Act's Special Projects of National Significance (SPNS) demonstrate and evaluate innovative methods of delivering health and support services to underserved people living with HIV disease. Seventeen of the SPNS sites reported on 4,804 people served during the past five years.  Only 15 percent of their participants reported earned income, and 30 percent said they had no income from any source. About two-thirds of SPNS participants reported Medicaid coverage (48 percent) or no health insurance (16 percent).  Seventy-three percent were people of color, and almost 57 percent had not completed high school.

1. Bozzette, S.A. et al., The Care of HIV-Infected Adults in the United States, New England Journal of Medicine, Volume 399, Number 26, p 1902, December 24, 1998.

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