Provider Update

Volume 18, Issue 1 

February/March 2001


Unisys Assumes Responsibility for Provider Enrollment Hospital Manual Update
New Vaccine Available to Physicians, KIDMED Providers, and Rural Health Clinics EPSDT Dental Program - Clarification Regarding Orthodontic Services
CommunityCARE Referrals/Authorizations Coverage of Osteogenic Bone Stimulators
HCPC Code Changes for DME Expansion of Medicaid Coverage for Specific Codes
Anesthesia for Laparoscopy Depo-Provera Codes
Policy and Procedure Clarification LADUR Education Article

Unisys Assumes Responsibility for Provider Enrollment

Effective March 1, 2001, the Department of Health and Hospitals will transfer its Provider Enrollment function to Unisys Corporation. As part of this transfer, the Department is implementing revised procedures that will enable enrollment applications to be processed more efficiently.

New policies and procedures include the following:
� All application forms MUST be completed in their entirety. If an application is submitted with incomplete or inaccurate information, the entire application package will be returned to the submitting provider with a cover letter identifying the needed information. The provider must correct the form(s) as needed and re-submit the entire enrollment application.
� Applications, updates, or any other changes to provider enrollment records MUST be submitted to the Unisys Provider Enrollment Unit in writing. (Requests for linkages of individual providers to group numbers will continue to require a completed PE-50 form.)
� Correspondence to the Unisys Provider Enrollment Unit MUST be mailed to : Unisys - Provider Enrollment Unit PO Box 80159 Baton Rouge, LA 70898-0159

If you have a pending application, there is no need to contact the new Unisys Provider Enrollment Unit. If the application is complete, it will be processed according to currently established guidelines. If it is incomplete, it will be returned to you for correction and resubmission.

Please read future Remittance Advice messages to learn more about this transition, including how to contact the new Unisys Provider Enrollment Unit. The new telephone numbers will be available on the current DHH Provider Enrollment Unit voice mail after March 1, 2001. We do not anticipate any interruption of service during this transition and look forward to serving your enrollment needs in the future.


Hospital Manual Update 

The Louisiana Medicaid Hospital Services Provider Manual issued June 1, 1995 has an error on page 4-16. The listing of ICD-9-CM code 69.52 used in abortions is incorrect. This was a typographical error and the code should read 69.51 - aspiration curettage of uterus for termination of pregnancy. A revised manual page has been issued. We apologize for any inconvenience this may have caused.


New Vaccine Available to Physicians, KIDMED Providers, and Rural Health Clinics

The Vaccines for Children Program (VFC), which is administered by the Office of Public Health (OPH) Immunization Program, has notified the Medicaid Program that the new pneumococcal vaccine, Seven Valent Pneumococcal Conjugate Vaccine (PCV7), is available through its program. Medicaid will now cover the administration of this vaccine under procedure code 90669 effective with date of service 11/01/2000. Medicaid covers only the administration fee since vaccines are available to providers at no charge to them from the VFC. The OPH has established a statewide policy that limits provision of this vaccine to only high risk children or presumed high risk children. We recommend that all providers contact the OPH Immunization Program at (504) 483-1900 for any inquiries related to their policy on this vaccine. Your Medicaid policy questions regarding this issue can be answered by calling (225) 342-3935. You may contact the Program Operation at (225)342-3935 if you have any questions regarding Medicaid policy on this issue.


EPSDT Dental Program-Clarification Regarding Orthodontic Services 
RA Message 1/2/01 and 1/9/01 - FIMS #6193

The limitations for orthodontic services covered under the Medicaid EPSDT Dental Program have not changed (See Dental Services Manual, Pages 4-16 and 4-17). Orthodontic treatment is covered only when treatment is considered medically necessary (i.e., cleft palate and/or lip, Crouzon's syndrome, Treacher-Collins syndrome, Pierre-Robin syndrome, hemi-facial atrophy, hemi-facial hypertrophy, and other craniofacial deformities, resulting in a physically handicapping malocclusion.) Orthodontic services for recipients having only crowded dentition, excessive overbite and/or overjet are not covered. The correction of isolated crossbites may be considered if the services can be performed in their entirety for $200 or less. 

All orthodontic services requests require prior authorization. If the dental provider determines that the recipient could possibly meet the specified criteria, he/she should refer the recipient to a participating Medicaid orthodontist. If referral assistance is required, the dentist may refer the recipient to the KIDMED and CommunityCARE Referral Assistance Hotline at 1-877-455-9955. If you have any questions regarding this matter, you may contact the LSU School of Dentistry Dental Medicaid Unit by calling (504)-619-8589.


CommunityCARE Referrals/Authorizations

Services provided to Medicaid recipients who are enrolled in the CommunityCARE Program must be provided or authorized by their primary care physicians (PCP). CommunityCARE eligibility may be determined by using the MEVS or REVS systems. If claims for services are not provided or authorized by the PCP responsible for the recipient's total medical care, they will be denied for payment with Error Code 106 (Provider not PCP or service not authorized by PCP). 

GENERAL INFORMATION
Referrals must be written. Should an instance occur when a verbal authorization is given, it must be followed up with a written referral.
� Both the PCP and the provider of services must maintain copies of signed written referrals in the recipient's record. 
� Referrals should be obtained prior to providing services with the exception of urgent/emergency care. In instances where a retroactive referral is requested, the PCP must either deny or issue the referral within 5-7 working days. The PCP will maintain a system for tracking referrals to monitor the status of requests and to maintain feedback from referral consultants.
� Referrals may be written for a single visit or for multiple visits over a time period not to exceed six months except for obstetrical care, which may be written for the term of the pregnancy plus the six week postpartum visit.
� Referrals should be for treatment/evaluation of a specific condition or for rule-out diagnosis. When a specialist requires additional diagnostic or other services (i.e. lab, pathology, radiology, etc.), it is his/her responsibility to provide a copy of the PCP's referral to the providers of those additional services.

SPECIFIC REFERRAL SITUATIONS
The following describes the CommunityCARE referral process for specific instances. For issues not addressed in this article regarding Medicaid or CommunityCARE coverage of services, the Unisys Provider Relations Unit may be contacted at 1-800-473-2783.
Emergency Services - These DO NOT REQUIRE prior authorization, but DO REQUIRE post review for authorization. Emergency services rendered to the CommunityCARE enrollee in the outpatient hospital setting are covered in accordance with the requirements of the Balanced Budget Act of 1997, using the prudent layperson standard. CommunityCARE, as a managed care entity, reserves the right to deny payment for services rendered when the presenting symptoms do not meet the prudent layperson definition. The PCP will retrospectively review medical screening exams and any associated diagnostic testing of enrollees whose presenting symptoms (including severe pain) or response to those symptoms meet the prudent layperson definition of an emergency medical condition. Emergency room face sheets and/or any supporting documentation should be forwarded to the PCP the following work day for review prior to the PCP issuing a written referral.
Inpatient Care - When an enrollee is hospitalized, it is the hospital's responsibility to provide a copy of the PCP's written referral for that admission to any other providers that will bill Medicaid for services related to that admission. 

Examples include the following:
When the PCP admits the enrollee to the hospital, a referral to the hospital must be provided. The hospital will provide a copy of the PCP's written referral to providers of specialty services that may be required in the course of that hospitalization (e.g. radiology, pathology, anesthesiology).When the PCP refers the enrollee to a surgeon, he/she must provide the surgeon with a written referral for the surgery. When the surgeon admits the enrollee, the surgeon provides a copy of the PCP written referral to the hospital. The hospital provides a copy of the written referral to the surgical assistant and to other required services. 

Note: A PCP's membership on the medical staff does not exempt a hospital from obtaining written referrals for inpatient or emergency services.

Referrals For Surgery (Inpatient/Outpatient) A referral issued for inpatient or outpatient surgery should routinely cover the surgery date and one followup visit. It is the surgeon's responsibility to ensure medical notes are sent to the PCP to be included in the enrollee's comprehensive medical record.

Administrative Referrals are sometimes required when an approved PCP change takes up to 40 days to process on REVS/MEVS. If an enrollee is linked to the wrong PCP due to an administrative error or a change in PCP, it may be best for the new CommunityCARE PCP to provide care for the enrollee. In these cases the current PCP may provide the enrollee with a 60-day administrative referral to the new PCP. Administrative referrals do not require documentation of follow up. When this type of administrative referral is issued, the new PCP may attach this referral to subsequent services referrals until the change in PCP is reflected in the system. The referral should clearly state "System Error" or "Change in PCP" as the reason for referral. Referrals issued for the "PCP change" should only be issued to another CommunityCARE PCP. Providers may confirm whether or not a provider is a CommunityCARE PCP by calling the toll-free number at the CommunityCARE contractors office, 1-800-609-3888.

EXEMPT SERVICES ( Do Not Require a Referral)
� Family Planning Services
� Dental Services for Children (routine, in office)
� Eye Care Services (eye glasses, ophthalmology, optometry)
� Psychiatric Services (Psychiatrist, Inpatient Psychiatric Hospital)
� Emergency and Non-Emergency Transportation
� Pharmacy Services 
� Mental Health Clinic Services
� Long Term Care Services (Nursing Home and ICF-MRs) 
� Home and Community Based Services
� Chiropractic (under 21 only)
� Case Management Services
� EPSDT Health Services
� Mental Health Rehabilitation

Some exempt services may require ancillary services that are not exempt from the referral requirements:

Physical examinations, laboratory, radiology, etc. performed in conjunction with psychiatric services are not exempt and the providers need a referral from the PCP in order to bill Medicaid. It is the responsibility of the psychiatric provider to obtain the referral from the PCP and furnish it to the ancillary providers.

If anesthesia services are performed in conjunction with dental services, the anesthetist will need a referral from the PCP to bill Medicaid. The dentist must obtain the referral from the PCP for the anesthetist.

BILLING FOR REFERRALS
In order for a provider to be reimbursed for claims associated with authorized referral services, the PCP's seven-digit authorization number must be on the claim form in the field designated below:
� In block 83A for Inpatient and Outpatient claims filed on the UB-92
� In block 17A for Physician/DME claims filed on the HCFA 1500
� In block 12 for claim type 05 (rehabilitation claims)
� In block 10 for claim type 06 (home health claims)
� EMC Billers should use the corresponding fields on their submissions

If the authorization number is not in the designated field on the claim form, the claim will be denied even if a copy of the referral is attached to the claim. Billing providers will receive a remittance advice stating that the reason for denial is Error/Edit Code 106, (Provider not PCP or service not authorized by PCP). Providers may call the Unisys Provider Relations Unit regarding this and other claims processing problems.

UNAUTHORIZED USE OF REFERRAL/AUTHORIZATION NUMBER
Use of a CommunityCARE provider's number for billing purposes without the appropriate written referral shall result in recoupment of the unauthorized reimbursements by the Medicaid Program. Submission of a fraudulent claim is punishable by fine and/or imprisonment. 


Coverage of Osteogenic Bone Stimulators

DHH has published a rule to add coverage of osteogenic bone growth stimulators to the DME Program. The stimulators are used to augment bone repair associated with either a healing fracture or bone fusion. The rule limits coverage only for non-invasive type of bone stimulators. Reimbursement for ultrasonic or invasive types of bone stimulators is not covered. Effective immediately, the Prior Authorization Unit of Unisys will authorize requests for payment for these services in accordance with the following criteria.

Non-Spinal, Non-Invasive Electrical Types (Code E0747)

These types of stimulators may be considered under the following circumstances:
1. The failure of long bone fractures to heal. A period of six months from the initial date of treatment must elapse before failure is considered to have occurred.
2. The failure of long bone fusions. A period of nine months from the initial date of treatment must elapse before failure is considered to have occurred; or
3. The treatment of congenital pseudoarthroses. There is no minimal time requirement after the diagnosis.

Spinal, Non-Invasive Electrical Types (Code E0748)

These types of stimulators may be considered:
1. When a minimum of nine months has elapsed since the patient had fusion surgery which resulted in a failed spinal fusion; or
2. When there is a history of a previously failed spinal fusion at the same site following spinal fusion surgery (meaning more than nine months have elapsed since fusion surgery was performed at the same level which is being fused again). As long as nine months have passed since the failed fusion surgery, this repeated fusion attempt requires no minimum passage of time for the application of the device; or
3. Following a multi-level spinal fusion (i.e. involving three or more contiguous vertebrae, such as L3-L5 or L4-S1). There is no minimum requirement for application after surgery.

Codes E0747 and E0748 are now on file for manual pricing. Reimbursement will be at billed charges up to 80% of the Medicare rate. The purchase price is entered on the file. The DME Program, however, will normally only consider renting bone growth stimulators unless the rental exceeds the price to purchase. Rental will be reimbursed up to 10% of the purchase amount on file per month. 


HCPC Code Changes for DME
RA Message 1/9/01, 1/16/01, and 1/23/01 - FIMS #6196

In order to maintain conformity to the HCPC coding system of Medicare and the Health Care Financing Administration, the following changes have been made to the Medicaid DME procedure codes: 

DISCONTINUED CODES 
Ostomy Supplies      Effective Date 
A4363 ..................  02/01/01 
K0137 ................... 02/01/01 
K0138 ................... 02/01/01 
K0139 ................... 02/01/01 
K0277 ................... 02/01/01 
K0278 ................... 02/01/01 
K0279 ................... 02/01/01 
K0419 ................... 02/01/01 
K0420 ................... 02/01/01 
K0421 ................... 02/01/01 
K0422 ................... 02/01/01 
K0423 ................... 02/01/01 
K0424 ................... 02/01/01 
K0425 ................... 02/01/01 
K0426 ................... 02/01/01 
K0427 ................... 02/01/01 
K0428 ................... 02/01/01 
K0429 ................... 02/01/01 
K0430 ................... 02/01/01 
K0431 ................... 02/01/01 
K0432 ................... 02/01/01 
K0433 ................... 02/01/01 
K0434 ................... 02/01/01 
K0435 ................... 02/01/01 
K0436 ................... 02/01/01 
K0437 ................... 02/01/01 

Nebulizers & Accessories Effective Date 
K0168 ........................... 03/01/01 
K0169 ........................... 03/01/01 
K0170 ........................... 03/01/01 
K0171 ........................... 03/01/01 
K0172 ........................... 03/01/01 
K0173 ........................... 03/01/01 
K0174 ........................... 03/01/01 
K0175 ........................... 03/01/01 
K0176 ........................... 03/01/01 
K0177 ........................... 03/01/01 
K0178 ........................... 03/01/01 
K0179 ........................... 03/01/01 
K0180 ........................... 03/01/01 
K0181 ........................... 03/01/01 

Suction Pump Access.    Effective Date 
K0192 .......................... 03/01/01 

CPAP & BIPAP            Effective Date 
E0452 ......................... 03/01/01 
E0453 ......................... 03/01/01 
K0193 ......................... 03/01/01 
K0194 ......................... 03/01/01 

Infusion Pump                Effective Date 
K0284 ........................ 03/01/01 
K0417 ........................ 03/01/01 

Oxygen Concentrators Effective Date 
E1400 ........................ 03/01/01 
E1401 ........................ 03/01/01 
E1402 ........................ 03/01/01 
E1403 ........................ 03/01/01 
E1404 ........................ 03/01/01 

Diabetic Shoe                Effective Date 
K0401 ........................ 03/01/01

ADDED CODES 
Ostomy Supplies          Effective Date 
A4370 ....................... 02/08/00 
A4371 ....................... 02/08/00 
A4372 ....................... 02/08/00 
A4373 ....................... 02/08/00 
A4374 ....................... 02/08/00 
A4375 ....................... 02/08/00 
A4376 ....................... 02/08/00 
A4377 ....................... 02/08/00 
A4378 ....................... 02/08/00 
A4379 ....................... 02/08/00 
A4380 ....................... 02/08/00 
A4381 ....................... 02/08/00 
A4382 ....................... 02/08/00 
A4383 ....................... 02/08/00 
A4384 ....................... 02/08/00 
A4385 ....................... 02/08/00 
A4386 ....................... 02/08/00 
A4387 ....................... 02/08/00 
A4388 ....................... 02/08/00 
A4389 ....................... 02/08/00 
A4390 ....................... 02/08/00 
A4391 ....................... 02/08/00 
A4392 ....................... 02/08/00 
A4393 ....................... 02/08/00 

Nebulizer & Accessories Effective Date 
A7003 .......................   01/01/00 
A7004 .......................   01/01/00 
A7005 .......................   01/01/00 
A7006 .......................   01/01/00 
A7007 ........................  01/01/00 
A7008 ........................  01/01/00 
A7009 ........................  01/01/00 
A7010 ........................  01/01/00 
A7011 ........................  01/01/00 
A7012 ........................  01/01/00 
A7013 ........................  01/01/00 
A7014 ........................  01/01/00 
A7015 ........................  01/01/00 
A7016 ........................  01/01/00 
A7017 ........................  01/01/00 

Suction Pump Access   Effective Date 
A7000 ........................ 01/01/00 
A7001 ........................ 01/01/00 
A7002 ........................ 01/01/00 

CPAP & BIPAP           Effective Date 
K0531 ........................ 01/01/00 
K0532 ........................ 01/01/00 
K0533 ........................ 01/01/00 
K0534 ........................ 01/01/00 

Infusion Pump               Effective Date 
E0779 ........................ 01/01/00 
E0780 ........................ 01/01/00 

Oxygen Concentrator Effective Date 
E1390 ...................... 01/01/00 

Diabetic Shoe             Effective Date 
A5508 ...................... 01/01/00


Expansion of Medicaid Coverage for Specific Codes

CPT Code J9160 - Effective for dates of service on or after January 1, 2001, Denileukin diftitox (ONTAK) for the treatment of persistent or recurrent cutaneous T-cell lymphoma is payable at a fee of $894.63 per 2 ml vial. The primary diagnoses for which this agent will be reimbursed are 202.1 and 202.2.
RA Message 1/2/01 and 1/9/01 - FIMS #6198 

CPT Code J9170 - Docetaxel (TAXOTERE) effective for dates of service on or after June 1, 2000 is payable at a fee of $253.72 per 20 mg. Effective with date of service November 1, 2000, the fee was increased to $266.48. The primary diagnoses for which this agent will be reimbursed are 162.0 through 162.9, 174.0 through 174.9, 175.0 through 175.9, 198.81, 231.2, and 233.0.
RA Message 1/2/01 and 1/9/01 - FIMS #6200

CPT Code 78810 - Effective for dates of service on or after November 1, 2000, CPT code 78810 (Tumor imaging, positron emission tomography, metabolic evaluation) is payable at a fee of $195.02. The professional component is payable at a fee of $78.00.
RA Message 1/16/01 and 1/23/01 - FIMS # 6188


Anesthesia for Laparoscopy 
RA Message 1/30/01 and 2/6/01 - FIMS # 6215

Effective for dates of service on or after October 1, 2000 CPT Code 58660 (Laparoscopy, surgical; with lysis of adhesions) has been assigned Anesthesia Base Units of 05.


Depo-Provera Codes
RA Message 12/27/00 and 1/2/ 01 - FIMS # 6190

Two codes for Depo-Provera are currently in payment status on our file, J9162 and J1055. Effective with date of service January 1, 2001, CPT code J9162 was placed in non-pay status, as it no longer appears on the Medicare Drug Injection List. Code J1055 will remain payable for Depo-Provera injections.


Policy and Procedure Clarification 
RA Message 1/16/01, 1/23/01, and 1/30/01 - FIMS # 6181

This is to provide clarification of existing policies and procedures for prior authorization requests for specialty eye wear which are billed under the procedure code X0089 for Medicaid recipients, under the age of 21. 

Contact lenses will not be approved unless medically necessary. When submitting Form PA-01 for contact lenses, you must also submit a prescription and documentation of medical necessity which also states that no other means can restore vision. We will continue to pay 85% of the billed charges for this procedure not to exceed $250.00. 

Specialty lenses, such as lenses with a higher index than those listed in the Vision Services Manual, will require a prescription and a statement of medical necessity with Form PA-01. These lenses will continue to be paid at 85% of the billed charges not to exceed $100.00. Polycarbonate lenses will not be approved unless they are medically necessary. The Form PA-01 should be submitted along with the prescription and a statement of medical necessity. We will continue to pay 85% of the billed charges for this procedure not to exceed $100.00. The fee for specialty lenses includes a standard metal or plastic frame. 

Procedure code X0089 is all inclusive; therefore, providers should not bill any separate eyeglass component codes. Eyeglasses that require a special frame will be considered if they are necessary in order to fit a child who has a certain medical condition or if the child is too small or large to accommodate a standard frame. The Form PA-01 should be submitted along with the prescription and a statement providing the reason for the necessity of the special frames. The only time that a frame should be listed on the Form PA-01 is if a specialty frame is being requested. We will continue to pay 85% of the billed charges not to exceed $100.00. 

Please note that all documentation regarding medical necessity must be from the eye care provider who wrote the prescription and must contain information specific to the needs of each individual recipient. If you are requesting more than one item listed above for a single pair of eyeglasses, you must list each item separately on the Form PA-01. A prior authorization request which contains all the required documentation should not take longer than 30 days to process. If you have any questions regarding the prior authorization process for eye wear, please contact Unisys Prior Authorization Unit by calling 1-800-488-6334.


LADUR Education Article

Treatment of HIV Infection: An Overview - Part I

Nancy M. Toedter, Pharm.D., Associate Professor of Clinical Pharmacy Practice 
The University of Louisiana at Monroe College of Pharmacy
Pharmacy Clinical Coordinator Glenwood Regional Medical Center West Monroe, Louisiana

ISSUES:

� Due to the availability of potent antiretroviral regimens, there has been a decline in AIDS incidence and deaths as well as an increase in the number of persons living with AIDS.
� The goals of antiretroviral therapy include suppression of viral load to undetectable levels, restoring immunologic function, improving the patient's quality of life, and reducing HIV-related illness and death.
� There are fifteen antiretrovirals from three different classes currently available in the U.S. for treating HIV infection. With combination therapy being the standard of care, great potential exists for serious drug-drug interactions, overlapping toxicities, and difficult dosing schedules.

Introduction
Acquired immunodeficiency syndrome (AIDS) is an illness that has attracted attention in the medical field, as well as in the general community, and is an area of medicine that is rapidly changing. AIDS was first described in the U.S. in 1981, and then in 1983, researchers isolated human immunodeficiency virus (HIV) as the pathogen causing AIDS.1 The first antiretroviral agent for treating HIV infection wasn't introduced until 1987; however since then, significant advances have been made in understanding this syndrome and its pharmacological management. The advent of potent combination antiretroviral regimens, particularly those containing a protease inhibitor or non-nucleoside reverse transcriptase inhibitor, has decreased the incidence of opportunistic infections and prolonged survival in HIV-positive patients. Once viewed as being uniformly fatal, HIV infection is now recognized as being a chronic, manageable disease. 

Recently, the Food and Drug Administration (FDA) approved a new antiretroviral agent, a new fixed-dose combination product, and a different formulation of an existing agent. As a result, there are currently fifteen antiretrovirals, from three different classes, available in the U.S. for treating HIV infection (Table 1) - six nucleoside reverse transcriptase inhibitors (NRTIs), three non-nucleoside reverse transcriptase inhibitors (NNRTIs), and six protease inhibitors (PIs). Additionally, there are two combination nucleoside products (zidovudine/lamivudine and zidovudine/lamivudine/abacavir) and one protease inhibitor (saquinavir) that has two formulations available. While currently available antiretroviral agents cannot eradicate HIV from an infected individual, attention is now being redirected toward the long-term management of this chronic illness. These three- or four- drug combination regimens, which have become the standard of care for treating HIV infection, can be very challenging for both the patient and practitioner because of the adverse effects, numerous drug interactions, and the complex dosing schedules. This two-part article reviews currently approved agents for treating HIV infection, because a better understanding of antiretroviral therapy will promote optimal patient care.

Epidemiology 
At the end of 1997, it was estimated that more than 30 million persons worldwide were living with HIV infection. Most of these persons live in sub-Saharan Africa (68%) or in South and Southeast Asia (20%), with less than 3% residing in North America and less than 2% in western Europe.2 Although the statistics are not as dramatic in the United States, when compared with developing countries, our nation has been heavily affected by HIV/AIDS. From 1981 through June 2000, a cumulative total of 753,907 persons were reported with AIDS in the U.S. and its territories. Of these, 83% were males, 17% were females, and 1.2% were children less than 13 years old. Through June 2000, 438,795 persons with AIDS have died.3 Estimates suggest that between 650,000 to 900,000 Americans were living with HIV infection in 1992, and at least 40,000 new cases of HIV infection occur each year in the U.S.4 

Louisiana is not immune to these statistics. As of April 2000, a total of 19,186 cumulative cases of HIV infection have been reported in Louisiana; this figure includes over 12,000 cumulative AIDS cases.5 Furthermore, in the recent CDC HIV/AIDS Surveillance Report (Vol. 11, No. 2), Louisiana ranked 10th highest in state AIDS case rates and 13th in number of AIDS cases reported in 1999.6 

Nationally, various HIV/AIDS trends have been noted. Men continue to account for the majority of AIDS cases (77% in 1999); however, cases among women are steadily increasing. For example, the proportion of AIDS cases reported among adult/adolescent women increased from 14% in 1992 to 23% in 1999, while the proportion of male AIDS cases decreased from 86% to 77%.6,7 The proportion of women infected heterosexually continues to increase, accounting for 40% of AIDS cases in 1999, thus continuing to surpass those infected through injection drug use.6 Regarding race/ethnicity, the proportional distribution of AIDS cases among racial groups has shifted since the start of the epidemic. While the proportion of AIDS cases among whites has decreased over time, disproportionate increases have been noted among blacks and Hispanics. For instance, from 1992 to 1999, the proportion of adult/adolescent AIDS cases reported in whites decreased from 48% to 32% in contrast to an increase from 33% to 47% among blacks.6,7 

Several epidemiological trends in HIV/AIDS morbidity and mortality have been identified. Throughout the 1980s and early-1990s, the incidence of AIDS-related opportunistic illnesses and AIDS deaths increased yearly. However, in 1996, AIDS incidence declined for the first time, dropping 6%, and AIDS deaths also decreased for the first time, dropping 23%.8 This favorable trend has been attributed to the availability of potent antiretroviral therapies. The decline in both AIDS incidence and deaths continued into 1998, and as a result of this trend, in 1997, HIV infection plummeted from the eighth to the fourteenth leading causes of death in the U.S.9 Although a decline in AIDS incidence and deaths continues, their rates of decline have been slowing. AIDS prevalence, however, continues to increase. At the end of 1999, approximately 320,000 persons were living with AIDS, which represents an 8% increase over the previous year.3 

Another trend involves the dramatic decline in the number of children diagnosed with AIDS. Perinatal AIDS cases peaked in 1992, then decreased 67% from 1992 to 1997. This declining trend in pediatric AIDS incidence has continued through 1999 and is associated with the increased use of zidovudine therapy during pregnancy and delivery to prevent perinatal HIV transmission.3,10

Etiology, Transmission, and Surrogate Markers 
Two types of HIV have been identified: HIV-1 and HIV-2. Although related, they are genetically and immunologically distinct. Their modes of transmission are similar, and both HIV types cause severe immunosuppression associated with AIDS. They differ mainly in that HIV-2 is found predominantly among heterosexual persons in West Africa; whereas, HIV-1 is the subtype found most commonly in the U.S. and will be the focus of this article.1,2 

There are three primary modes of HIV transmission: sexual contact, exposure to blood and blood products, and perinatal transmission from an infected mother to her infant. Of these, sexual contact is the most common route of HIV transmission throughout the world. In the U.S., male-to-male sexual transmission accounts for the majority of AIDS cases (34% in 1999), followed by injecting drug use (22% in 1999). Heterosexual transmission is on the rise, accounting for 15% of new AIDS cases in 1999.1,6 

Two surrogate markers are commonly used in assessing disease progression and in monitoring response to antiretroviral treatment: CD4 cell count and plasma HIV RNA levels (viral load). Since HIV attacks and destroys the immune system, specifically CD4+ T lymphocytes, depletion of these cells has been associated with the development of opportunistic infections (OIs) and other AIDS malignancies. Therefore, the CD4 count indicates the extent of immune system damage already suffered due to HIV infection and is primarily used to determine when to start or discontinue prophylaxis for OIs.11,12 Plasma HIV RNA levels (viral load) directly quantify the amount of virus-producing cells in the plasma and indicate the magnitude of active viral replication taking place. Viral load is a stronger predictor of disease progression and is valuable for determining when to initiate antiretroviral therapy and for monitoring response to therapy.11,12,13,14 Measuring both HIV RNA levels and CD4+ T-cell counts are useful in managing HIV-infected patients.

Goals of Therapy 
The approach to treating patients with HIV infection has dramatically changed over the years. Monotherapy with nucleoside reverse transcriptase inhibitors, which was once standard practice in managing HIV patients, is now considered suboptimal and is no longer recommended. Potent antiretroviral combination regimens that suppress plasma viral load to undetectable levels (currently defined as < 50 RNA copies/mL) are now the standard of care and have resulted in significant declines in HIV-related morbidity and mortality. These regimens, termed highly active antiretroviral therapy (HAART), generally include two nucleoside reverse transcriptase inhibitors combined with either one or two protease inhibitors or a non-nucleoside reverse transcriptase inhibitor, and they are initiated early in the disease process. Therefore, the goals of HIV therapy should be maximal and durable suppression of viral load, restoration and/or preservation of immunologic function, improvement of the patient's quality of life, and reduction of HIV-related illness and death.15 

There are fifteen antiretrovirals from three different classes currently available in the U.S. for treating HIV infection. These agents target two sites in the HIV replication cycle - inhibition of the reverse transcriptase and protease enzymes. Although potent, these agents cannot eradicate HIV infection because of the extremely long half-life of cellular reservoirs (resting CD4+ T cells).16,17,18 However, when used in combination regimens, these antiretrovirals can decrease viral load, delay immunologic decline, and prolong life. A brief discussion of the currently available antiretrovirals follows.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 
NRTIs were the first class of antiretroviral agents approved for treating HIV infection. They work early in the viral replication cycle by inhibiting reverse transcriptase, an enzyme unique to retroviruses, which synthesizes DNA from viral RNA. By blocking the initial phase of viral replication, these agents slow or prevent HIV replication in newly infected cells but do not affect chronically infected cells (cells where the HIV genomes are already integrated into the host genome).19,20 NRTIs are dideoxynucleoside analogs and are essentially prodrugs, requiring conversion to their active triphosphate forms by cellular kinases in order to exert their effect. As triphosphates, they compete with endogenous deoxynucleotides for binding to HIV reverse transcriptase. In addition to competitive inhibition, NRTIs also cause premature chain termination following incorporation into the growing viral DNA strand.21,22 

As outlined in Table 2, there are currently six NRTIs approved for treating HIV infection, and they include zidovudine, didanosine, zalcitabine, stavudine, lamivudine, and abacavir. Additionally, there are two combination nucleoside analog products available -- Combivir and Trizivir. Traditionally, two NRTIs are used in combination with either a PI or NNRTI. NRTIs are relatively well tolerated and are not associated with the extensive drug interactions seen with the other antiretroviral classes. Average wholesale price (AWP) for NRTIs usually averages approximately $200 - $350 per month.23 

Zidovudine (Retrovir, AZT, ZDV) was approved by the FDA in 1987 and became the first antiretroviral agent available for treating HIV infection. It is currently the only antiretroviral with a parenteral formulation. It has established efficacy in prevention and treatment of AIDS dementia complex due to its ability to penetrate the blood-brain barrier.24,25 Additionally, zidovudine has demonstrated efficacy in preventing perinatal HIV transmission from an infected mother to her child and as part of a combination regimen for postexposure prophylaxis of health care workers following an occupational exposure to blood and other body fluids that may contain HIV.26,27 Zidovudine can be combined with other NRTIs, including didanosine, lamivudine, or zalcitabine. However, it should not be used with stavudine because this combination may be antagonistic, resulting in a decline in CD4+ T cell counts.18,28 Zidovudine is dosed as 600 mg per day in two or three divided doses, and may be taken without regard to meals.15 It is also available in two fixed-dose combination products: zidovudine/lamivudine (Combivir) and zidovudine/lamivudine/abacavir (Trizivir). Zidovudine has a limited duration of effectiveness because resistance to zidovudine often occurs after prolonged exposure and in those patients with advanced disease.21,22 Major toxicities of zidovudine, which are seen more commonly in those with advanced HIV disease, include anemia and neutropenia. Other adverse effects include nausea, vomiting, headache, fatigue, confusion, malaise, and insomnia. Myopathy may also occur after prolonged therapy.15,22,29 

Didanosine (Videx, ddI) was the second drug approved for treating HIV infection. It is used primarily in combination with zidovudine or stavudine, plus a PI or NNRTI. It has also been combined with hydroxyurea, resulting in enhanced anti-HIV activity of didanosine. It should not be combined with zalcitabine because of overlapping toxicities.15,29,30 Didanosine is inactivated by gastric acid, so it is formulated with an antacid buffer. However, as this buffering component may interfere with the absorption of certain medications requiring an acidic environment, such as dapsone, ketoconazole, itraconazole, doxycycline, fluoroquinolones, delavirdine, indinavir, and others, they should be administered at least two hours apart.29,30 Major toxicities of didanosine include peripheral neuropathy, pancreatitis, and gastrointestinal disturbances. The risk of pancreatitis may be increased when used concomitantly with stavudine.29,31 Didanosine is usually administered twice daily on an empty stomach; however, last year it was FDA-approved for once-daily dosing to simplify regimens. It is important to note that for either regimen, patients must take at least two chewable/dispersible tablets per dose to provide adequate buffering for proper absorption.31 Unfortunately, this past summer, study results demonstrated that the virologic response with once-daily dosing was significantly lower than that observed in the comparator group. Therefore, the preferred dosing frequency with this original buffered formulation is twice daily.32 In November 2000, a new formulation of didanosine received FDA approval -- Videx EC delayed-release capsules. Rather than containing a buffering component, these capsules contain enteric-coated beadlets designed to protect didanosine against gastric acid degradation. Videx EC is administered once daily on an empty stomach, and this new formulation causes less diarrhea, is associated with fewer drug interactions, and has improved taste when compared with the buffered formulation.33 

Zalcitabine (Hivid, ddC), approved by the FDA in 1992, seems to be the weakest of the NRTIs and is not frequently used. Its short plasma half-life necessitates three-times-daily dosing. Toxicities with zalcitabine are similar to didanosine: painful peripheral neuropathy and pancreatitis. The peripheral neuropathy occurs more frequently with zalcitabine; whereas, pancreatitis occurs more often with didanosine. Other adverse effects include rash, stomatitis, and esophageal ulceration. Zalcitabine should not be combined with didanosine or stavudine because of overlapping toxicities, and it should not be used with lamivudine because this combination has not been well studied.18,22,29,30 

Stavudine (Zerit, d4T) was FDA-approved in 1994 and is used both in initial combination regimens and after failure of or intolerance to zidovudine-containing regimens. It is frequently given in combination with didanosine or lamivudine, plus a PI or NNRTI. Stavudine should not be combined with zalcitabine because of overlapping toxicities or used with zidovudine because of in vitro antagonism.15,29,30 Similar to zidovudine, stavudine may penetrate the blood-brain barrier and may prevent neurological deterioration.24,28 Administered twice daily, this drug is generally well tolerated with the major toxicity being a dose-related peripheral neuropathy, as seen with didanosine and zalcitabine. Symptoms usually resolve after drug discontinuation or dosage reduction. Other adverse effects include transaminase elevations and rarely pancreatitis, although the latter toxicity may be more common when stavudine is combined with didanosine. Unlike zidovudine, hematological toxicities are infrequent.15,29,30 

Lamivudine (Epivir, 3TC) was approved in 1995 as the fourth NRTI. It is also indicated for the treatment of hepatitis B infection. Lamivudine is frequently used in combination with zidovudine, stavudine, or didanosine plus a PI or NNRTI.15,30 The combination of lamivudine and zidovudine is particularly synergistic because lamivudine may cause a previously zidovudine-resistant strain to become sensitive to zidovudine. This NRTI should only be used in potent combination regimens that maximally suppress viral load to prevent the rapid emergence of lamivudine resistance. Lamivudine is probably the best tolerated NRTI, with only mild adverse effects reported, including gastrointestinal intolerance, headache, and fatigue.12,29,30 For improved compliance and reduced pill burden, it is available in two fixed-dose combination products - zidovudine/lamivudine (Combivir) and the newly-released zidovudine/lamivudine/abacavir (Trizivir). 

Abacavir (Ziagen, ABC) is the newest nucleoside analog, approved in 1999. It has several advantages over other NRTIs: penetration into the central nervous system, twice-daily dosing, slow development of resistance, and few drug interactions. Abacavir appears to be the most potent nucleoside analog to date, particularly in treatment-na�ve patients. Although studied in various combination therapies, including those with PIs, the regimen of abacavir plus zidovudine and lamivudine is best characterized. This triple NRTI regimen has raised CD4 counts and lowered viral load to undetectable levels in the majority of treatment-na�ve patients. However, abacavir may be less effective in patients with extensive prior exposure to NRTIs. Although generally well tolerated, abacavir can cause a potentially fatal hypersensitivity reaction, which has been reported in about 5% of patients. Symptoms, which typically appear within the first six weeks of therapy, include fever, skin rash, fatigue, nausea, vomiting, diarrhea, abdominal pain, dyspnea, or cough. Once discontinued secondary to this reaction, abacavir should never be resumed because re-exposure can result in more severe, and potentially fatal, reactions within hours.18,29,30,34,35 Since Trizivir contains an abacavir component, the hypersensitivity reaction may also occur with this combination product.36 

In November 1999, adefovir (Preveon), a nucleotide reverse transcriptase inhibitor with once-daily dosing and activity against a broad range of viruses, did not receive FDA approval for treatment of HIV infections due to its modest antiviral activity and its association with nephrotoxicity. The manufacturer has since halted development of adefovir for HIV infections.29,37 

This article reviewed current epidemiological trends, goals of therapy, and the six NRTIs currently available. The April 2001 issue of the Provider Update will discuss non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and treatment strategies.

*There are two formulations of saquinavir: hard-gel capsule (HGC) and soft-gel capsule (SGC).

 

References

1. Chamberland ME, Ward JW, Curran JW. Epidemiology and prevention of AIDS and HIV infection. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 4th ed. New York; Churchill Livingstone, 1995:1174-1203.

2. Jones JL, DeCock KM, Jaffe HW. Current trends in the epidemiology of HIV/AIDS. In: Sande MA, Volberding PA, eds. The Medical Management of AIDS. 6th ed. Philadelphia, Pennsylvania; W.B. Saunders Co., 1999:3-22.

3. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report, June 2000;12(No. 1):1-41.

4. Karon JM, Rosenberg PS, McQuillan G, et al. Prevalence of HIV infection in the United States, 1984 to 1992. JAMA. 1996;276:126-131.

5. State of Louisiana Office of Public Health HIV/AIDS Services.

6. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report, December 1999;11(No. 2):1-44.

7. CDC. Update: trends in AIDS incidence, deaths, and prevalence - United States, 1996. MMWR. 1997;46:165-173.

8. CDC. Update: trends in AIDS incidence - United States, 1996. MMWR. 1997;46:861- 867.

9. CDC. Deaths: final data for 1997. NVSS. 1999;47:1-10.

10. Lindegren ML, Byers RH, Thomas P, et al. Trends in perinatal transmission of HIV/AIDS in the United States. JAMA. 1999;282:531-538.

11. Saag MS, Holodniy M, Kuritzkes DR, et al. HIV viral load markers in clinical practice. Nat Med. 1996;2:625-629.

12. National Institutes of Health (NIH) Panel. Report of the NIH panel to define principles of therapy of HIV infection. Ann Intern Med. 1998;128:1057-1078.

13. Mellors JW, Kingsley LA, Rinaldo CR, et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med. 1995;122:573-579.

14. Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med. 1997;126:946-954.

15. Department of Health and Human Services and the Henry J. Kaiser Family Foundation. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. January 28, 2000. Internet edition. (http://www.hivatis.org)

16. Schrager LK, D'Souza MP. Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy. JAMA. 1998;280:67-71.

17. Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5:512-517.

18. Carpenter CCJ, Cooper DA, Fischl MA, et al. Antiretroviral therapy in adults: updated recommendations of the International AIDS Society - USA Panel. JAMA. 2000;283:381- 390.

19. Fischl MA. Treatment of HIV infection. In: Sande MA, Volberding PA, eds. The Medical Management of AIDS. 4th ed. Philadelphia, Pennsylvania; W.B. Saunders Co., 1995:141- 160.

20. Hirsch MS, D'Aquila RT. Therapy for human immunodeficiency virus infection. N Engl J Med. 1993;328:1686-1695.

21. Corey L. Therapy of HIV infection. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 4th ed. New York; Churchill Livingstone, 1995:1267- 1280.

22. Threlkeld SC, Hirsch MS. Antiretroviral therapy. Med Clin North Am. 1996;80:1263-1282.

23. Cardinale V, ed. Drug Topics Red Book. Montvale, NJ; Medical Economics Co., Inc., 1999.

24. Portegies P. HIV-1, the brain, and combination therapy. Lancet. 1995;346:1244-1245.

25. Price RW. Neurological complications of HIV infection. Lancet. 1996;348:445-452.

26. Centers for Disease Control and Prevention. Public Health Service task force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR. 1998;47(No.RR-2):1-30.

27. Centers for Disease Control and Prevention. Public Health Service guidelines for the management of health-care worker exposures to HIV and recommendations for postexposure prophylaxis. MMWR. 1998:47(No. RR-7):1-28.

28. BHIVA Guidelines Co-ordinating Committee. British HIV Association guidelines for antriretroviral treatment of HIV seropositive individuals. Lancet. 1997;349:1086-1092.

29. Anon. Drugs for HIV infection. Med Lett Drugs Ther. 2000;42:1-6.

30. Deeks SG, Volberding PA. Antiretroviral therapy. In: Sande MA, Volberding PA, eds. The Medical Management of AIDS. 6th ed. Philadelphia, Pennsylvania; W.B. Saunders Co., 1999:97-115.

31. Didanosine (Videx�) package insert. Princeton, NJ: Bristol-Myers Squibb; October 1999.

32. Medscape Reuters Medical News (http://pharmacotherapy.medscape.com/reuters/ prof/2000/08/08.11/20000811rglt008.html)

33. Didanosine (Videx EC) package insert. Princeton, NJ: Bristol-Myers Squibb; November 2000.

34. Abacavir (Ziagen�) package insert. Research Triangle Park, NC: Glaxo Wellcome; January 2000.

35. Levien TL, Baker DE. Abacavir (Ziagen). Pharm Let. 1999;15:11.

36. Kehoe WA. Combination abacavir, lamivudine, and zidovudine: Trizivir. Pharm Let. 2000;16:71.

37. Mellors JW. Adefovir for the treatment of HIV infection: if not now, when? JAMA. 1999;282:2355-2356.