The United States Department of Health and Human Services (DHHS) first published Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
on April 24th, 1998. Commonly referred to as the DHHS Guidelines or simply The Guidelines, they represent the consensus opinion of the Panel on Clinical Practices for Treatment of HIV. The Panel, which is referred to many times is this article, is appointed and convened by the DHHS and is composed of basic and clinical researchers as well as clinicians, participants from the DHHS, and nonvoting observers. The panel has monthly conference calls and meets in person at least twice per year to review publications and information from scientific meetings and to issue updates as new information regarding the treatment of HIV emerges. Not only do these guidelines provide the most up-to-date information regarding HIV care, they have also helped to set an acceptable standard of care for the treatment of HIV in the United States, which would also apply to the care of persons incarcerated in jails and prisons. The most recent update of the guidelines was published on October 29th, 2004 and is available at www.hhs.gov
. This article will serve to summarize those modifications of the guidelines that are relevant to correctional health care providers.
What Is New in This Version of the Guidelines
Changes in recommendations in this latest revision have to do with the initiation of antiretroviral therapy (ART) in ART-naive patients. These include an increase in the viral load recommendation to defer or consider therapy from 55,000 copies/mm3
to 100,000 copies/mm3
in asymptomatic patients with a CD4 cell count greater than 350 cells/mm3
. Stavudine has been changed from a "preferred" to an "alternative" agent; and tenofovir and lamivudine (or emtricitabine) are now recommended as preferred or alternative nucleoside (or nucleotide) backbones in protease inhibitor (PI) as well as nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens.
Additions to The Guidelines include a section on special populations; a discussion on discontinuation or interruption of ART, and several new tables showing data about the probability of progressing to AIDS, data from 48-week treatment trials, and revised tables on ART associated adverse events.
Any mention of hydroxyurea has been deleted from The Guidelines since the Panel feels it should limit its commentary to FDA-approved agents with indications for the treatment of HIV infection.
These changes and additions will be discussed in the general context of the primary care of HIV infected patients outlined in this update.
Expertise in the Treatment of HIV Infection
The guidelines continue to emphasize the importance of HIV expertise in "clinical care" since multiple studies have shown better outcomes when HIV-experienced treaters care for HIV infected patients. The Panel recommends HIV primary care by a clinician with at least 20, but preferably 50 HIV-infected patients and the guidelines also suggest that these HIV providers fulfill CME requirements on HIV-related topics.
The basic pretreatment "intake" evaluation for HIV care is aimed at confirming HIV infection and whether it is acute, identifying co-infections, and assessing the overall health of the patient. A complete history and physical examination should be performed. Factors that are known to affect adherence to therapy, including substance abuse, economic factors, need for social support, psychiatric illness, and other co-morbidities should be identified and if present, managed with available resources. The initial laboratory evaluation should include HIV antibody testing if confirmation of infection is not available, CD4 cell count, plasma HIV RNA, CBC, chemistry profile, transaminase levels, BUN and creatinine, urinalysis, serologic testing for syphilis, tuberculin skin testing, fasting blood glucose, serum lipids levels and serologies to measure antibodies to Toxoplasma gondii, Hepatitis A, B, and C. Women should have a PAP test. Testing for infection with Chlamydia trachomatis and Neisseria gonorrhea is optional and a chest radiograph should be performed if clinically indicated.
CD4 Cell Count and Viral Load
The CD4 cell count and the plasma HIV RNA to measure HIV viral load (VL) remain the two key serologic markers that are routinely used to determine when to initiate ART and to monitor ongoing efficacy of treatment. In general, VL and CD4 should be monitored every three to four months with more frequent assessments of the VL occurring when ART is initiated or changed.
The Panel recommends that VL be measured immediately before instituting or changing treatment and again two to eight weeks after treatment initiation or change. The results of this test help guide treatment and therefore limitations on VL testing that may be imposed in correctional settings (such as once every three months) would not apply in this situation. The primary goal of therapy remains a reduction in VL below the limits of detection and this can be achieved within 16-24 weeks of initiation of therapy.
The Food and Drug Administration has approved three VL assays, any of which can be used (most correctional systems will have selected one for use by all of their practitioners). Since VL testing can be used to evaluate control of HIV, "ultrasensitive" tests (that measure VL down to the lowest number of copies/mm3) should be used when changing therapy or evaluating the effectiveness of therapy. Available VL assays are summarized in Table 1.
Table 1. U.S. FDA Approved VL Assays
When to Treat
summarizes Panel recommendations for initiation of ART. The primary change in these recommendations is the increase in VL from 55,000 to 100,000 copies/mm3
as a cutoff for when to consider initiation of therapy. This trend towards delaying therapy based on VL determination is supported by data demonstrating that the risk for progression to AIDS within six months is greatest in those with a VL higher than 100,000 copies/mm3
whose CD4 cell count is less than 200 cells/mm3
. Conversely, in most individuals who have VL less than 100,000 copies/mm3
and a CD4 cell count greater than 350 cells/mm3
, the risk of progression to AIDS within six months is less than 2%.
Table 2. Recommendations for Initiating ART
In patients who are in care and having regular monitoring of VL, CD4 cell count, and clinical status, deferring therapy can provide extra time for addressing issues of substance use, psychiatric illness, other co-morbidities and extra time for education and preparing the patient to accept potent combination therapy aimed at suppressing VL to undetectable levels. The guidelines were changed in the hope that deferring therapy will decrease the long-term complications of ART by decreasing total exposure time to ART drugs. The correctional clinician should schedule regular follow up visits to monitor the patients' readiness for therapy. These visits provide an additional opportunity for education about the risks and benefits of ART.
Initial Combination Regimens for the Antiretroviral-Naive Patient
There are currently 20 different drugs belonging to four different classes that can be used to create combination regimens that are potent enough to suppress plasma viremia to nondetectable levels. These four classes are nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and fusion inhibitors (FI). The Panel prefers to call these combinations "potent combination ART" rather than Highly Active Antiretroviral Therapy (HAART). Current recommendations for treatment combinations are organized based on the three types of regimens for which there is information from clinical trials and clinical experience. These three combinations are NNRTI-based (1 NNRTI +2 NRTI), PI-based (1-2 PI + 2 NRTI), and triple NRTI-based regimens.
The panel defines a "preferred" regimen as one where clinical trial data have demonstrated efficacy and durability with acceptable tolerability and ease of use. An "alternative" regimen is defined by the Panel as a regimen that is efficacious, but has disadvantages compared to preferred regimens in terms of antiviral activity, durability, tolerability, or ease of use.
Efavirenz (Sustiva) and lopinavir/ritonavir fixed dose combination (Kaletra) remain the preferred NNRTI and PI for initial therapy. With regard to the NRTI backbone, stavudine has been moved from the preferred to the alternative list due to increasing evidence of adverse events. Tenofovir (Viread) and lamivudine (3TC) (or emtricitabine [FTC]) is recommended as a preferred and alternative NRTI backbone for both NNRTI- and PI-based regimens. This is the first time that emtricitabine has appeared as either a preferred or alternative agent in the guidelines.
Management of the Treatment-Experienced Patient
A full discussion of the management of treatment-experienced patients is beyond the scope of this article. However, the Panel recommends that resistance testing and expert advice should be part of this management. For more information, see the December 2004 issue of IDCR
, article by Dr. Ian Frank "Use of HIV Resistance Testing in Antiretroviral Therapy Decision Making
." A summary of the Panel's recommendations for experienced patients follows:
- Although most patients experience benefits from taking antiretroviral regimens, adherence, intolerance/toxicity and pharmacokinetic issues may complicate therapy and virologic failure or treatment-limiting toxicity occur commonly.
- Evaluation of ART failure should include assessing the severity of HIV disease of the patient; the antiretroviral treatment history, including the duration, drugs used, antiretroviral potency, adherence history, and drug intolerance/toxicity; and the results of current and prior drug resistance testing.
- Virologic failure on treatment can be defined as a confirmed HIV RNA level >400 copies/mm3 after 24 weeks, >50 copies/mm3 after 48 weeks, or repeated HIV RNA level >400 copies/mm3 after prior suppression of viremia to <400 copies/mm3.
- In managing virologic failure, the provider should make a distinction between limited, intermediate, and extensive prior treatment exposure and resistance.
- The goal of treatment in those with limited or intermediate prior drug exposure and whose viral isolates demonstrate limited or intermediate drug resistance is to re-establish maximal virologic suppression.
- The goal of treatment in those with extensive prior drug exposure and whose viral isolates demonstrate extensive drug resistance where viral suppression is difficult or impossible to achieve with currently available drugs is preservation of immune function and prevention of clinical progression.
- Assessing and managing a patient with extensive prior antiretroviral experience and drug resistance who is experiencing treatment failure is complex and expert advice is critical.
Table 3. Preferred and Alternative Regimens
Treatment Interruption and Reinstitution Based on CD4 Cell Count (CD4 Guided Therapy)
The new guidelines briefly discuss the option of discontinuing successful ART in patients whose treatment was started when the CD4 cell count was >350 cells/mm3
and who might not meet recommendations for initiating ART by today's guidelines. Although no large, long term studies have examined this strategy, several small studies and case reports seem to indicate that there is little risk of resistance following a single episode of treatment interruption. When this strategy is employed, a target CD4 count at which to resume therapy should be discussed with the patient ahead of time. The patient needs to know that there will be an increase in VL that may be associated with an increased risk of transmission to sexual and needle-sharing partners.
Special Populations Section
This newly added section presents discussion on considerations for ART in HIV-infected adolescents, injection drug users, HBV and HCV co-infected patients and HIV infected patients with tuberculosis. Although these sections address some of the special issues faced in correctional HIV care, other issues faced in corrections such as method of pill distribution, educational needs of the correctional population, and continuity of care upon discharge are not addressed.
The new guidelines that were released in October 2004 push back the criteria for initiation of treatment and describe new recommendations for the initiation of treatment. It is important for the correctional provider to understand that the guidelines are a "living document" and can be expected to be modified on a yearly basis or more frequently as further research is conducted. Important changes to the guidelines will be noted in IDCR
, and are also available at the DHHS website (www.hhs.gov
). The document provides a wealth of information and should be required reading for all correctional HIV providers. If perusing the greater than 100 page documents seems overwhelming, one might opt for a more thorough reading of the black boxes in the text of the document that summarize the recommendations of the Panel and a review of the tables (these start on page 41). And finally, these guidelines provide a framework for treatment, which must involve a partnership with the patient. Most correctional HIV patients present with co-morbidities that complicate treatment -- these will be addressed in future issues of IDCR
David Paar, M.D., is Director of HIV Care for University of Texas Medical Branch at Galveston. Disclosures: Consultant: Ortho Biotech, Grant/Research; Support: GlaxoSmithKline, Agouron, Merck, DCHD, Serono, Gilead, Chiron Corp, Boehringer-Ingelheim, Abbott Labs, Bristol-Myers Squibb; Speaker's Bureau: Roche, Bristol-Myers Squibb, Ortho Biotech.