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Am Fam Physician. 2000;62(3):661-663

The U.S. Department of Health and Human Services (HHS) has updated guidelines for antiretroviral therapy in adults and adolescents with human immunodeficiency virus (HIV) infection. The guidelines were developed by the 38-member Panel on Clinical Practices for Treatment of HIV Infection, which was convened by HHS and the Henry J. Kaiser Family Foundation. Originally published in 1998, the guidelines provide recommendations on when to start antiretroviral drug therapy, what drugs to use, when to change therapy and therapeutic options when a change is made in the antiretroviral regimen. Also included are recommendations for laboratory monitoring, including plasma HIV RNA load, CD4 T-lymphocyte count and drug resistance.

The document, titled “Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents,” is available at the HIV/AIDS Treatment Information Service Web site ( Single copies may be ordered by calling 800-448-0440 (or 301-519-0459 for international callers) or by sending an e-mail request to

The guidelines contain a new section on goals of therapy and now categorize some of the antiretroviral drug regimens as “strongly recommended.” Strongly recommended agents are those that the panel members believe can accomplish many of the therapeutic goals while causing minimal negative effects on quality of life. Drugs that are effective in viral suppression but greatly interfere with quality of life are now categorized as “recommended as alternatives.” The guidelines also discuss special considerations for antiretroviral therapy in adolescents, during pregnancy, in acute HIV infection and in advanced disease.

The following text highlights information on the goals of antiretroviral therapy, on initiating therapy in asymptomatic and symptomatic HIV disease, on changing the regimen because of therapeutic failure and on determining appropriate dosages for adolescents.

Goals of Antiretroviral Therapy

The guidelines state that the primary goals of antiretroviral therapy are to maintain maximal suppression of the viral load (i.e., fewer than 50 copies per mL), restore or preserve immunologic function, improve quality of life and reduce HIV-related morbidity and mortality. While a reduction in plasma viremia accounts for much of the clinical benefits of antiretroviral therapy, the guidelines note that the goal of suppressing viral replication as much as possible and for as long as possible must be balanced against the need to preserve effective treatment options. According to the guidelines, a strategy of switching to other antiretroviral regimens because of any detectable level of plasma viremia may rapidly exhaust the treatment options. In addition, the guidelines note that a favorable CD4 response can occur with incomplete suppression of the viral load. Thus, incomplete viral load suppression in the presence of sustained improvement in the CD4 count may not indicate a poor prognosis. This factor should be a consideration when evaluating the need to change antiretroviral therapy.

According to the guidelines, predictors of a virologic response to antiretroviral therapy include low baseline viremia and a high baseline CD4 count, a rapid drop in viremia, a decline of viremia to fewer than 50 HIV RNA copies per mL and adequate serum levels of antiretroviral drugs. Adherence to the drug regimen is also an important factor in achieving a low viral load. The guidelines point out that new dosing strategies, with a reduction in the number of pills and dose frequency, have been found to be equivalent to standard dosing schedules.

The guidelines discuss the benefits of sequencing the drugs so that future treatment options are kept open. For example, the use of class-sparing regimens preserves one or more classes of drugs for later use, possibly extending the overall long-term effectiveness of available antiretroviral therapy. The report states that testing for drug resistance is helpful in selecting a different antiretroviral regimen in patients who exhibit virologic failure.

Initiating Antiretroviral Therapy in Asymptomatic HIV Infection

According to the guidelines, antiretroviral therapy should be instituted aggressively, with the goal of suppressing the plasma viral load to undetectable levels. In general, antiretroviral therapy should be offered to any patient with fewer than 500 CD4 cells per mm3 or more than 10,000 copies of HIV RNA per mL by bDNA assay or more than 20,000 copies per mL by RT polymerase chain reaction. Two measurements of the CD4 and HIV RNA are recommended to ensure accuracy of the test results.

The guidelines recognize that there are two approaches to initiating antiretroviral therapy in asymptomatic patients: an aggressive approach of treating most patients early in the course of HIV infection and a more cautious approach of delaying therapy because the risk of progression is deemed to favor observation. With the aggressive approach, antiretroviral therapy would be started in all patients with fewer than 500 CD4 cells per mm3. Therapy would also be instituted in patients with higher CD4 counts but with more than 10,000 or 20,000 copies of HIV RNA per mL (depending on the method of testing). With the conservative approach, treatment would be delayed in asymptomatic patients with CD4 counts below 500 cells per mm3 and low but detectable levels of viremia, such as 18,000 copies of HIV RNA per mL. The guidelines state that the patient should make the final decision regarding the initiation of antiretroviral therapy.

The guidelines identify strongly recommended regimens such as those that include indinavir, nelfinavir, ritonavir plus saquinavir, or efavirenz in combination with two nucleoside reverse transcriptase inhibitors (NRTI), such as stavudine plus lamivudine or didanosine or zidovudine plus lamivudine or didanosine. While a protease inhibitor plus two NRTIs may be considered the preferred initial regimen by many physicians, the guidelines state that many other physicians would argue that a regimen of efavirenz plus two NRTIs is preferred because the potential toxicities associated with protease inhibitors may be avoided for a long time.

The guidelines state that plasma HIV RNA levels should be measured immediately before initiation of antiretroviral therapy and again in two to eight weeks after the start of therapy. In most patients, a large decrease in the viral load should occur after two to eight weeks of therapy. The viral load should continue to decline, with the levels becoming undetectable (less than 50 HIV RNA copies per mL) after 16 to 20 weeks of therapy. The rate of the decline in the viral load is affected by the baseline CD4 count, the initial viral load, the potency of the regimen, the patient's adherence to the regimen and previous exposure to antiretroviral drugs and the presence of opportunistic infections. Plasma HIV RNA levels and CD4 counts should subsequently be measured every three to four months during follow-up.

Initiating Antiretroviral Therapy in Advanced HIV Disease

Antiretroviral therapy is recommended in all patients with advanced HIV disease, which is defined as acquired immunodeficiency syndrome (AIDS), and in all patients with symptomatic HIV infection, such as thrush or unexplained fever, but without AIDS. Because of the likelihood of concomitant disease, the choice of which antiretroviral agents to use in patients with advanced HIV disease must be made in light of potential drug interactions and overlapping drug toxicities. For example, protease inhibitors adversely affect the metabolism of rifampin, while rifampin reduces the blood level of protease inhibitors.

Changing Antiretroviral Therapy

The guidelines stress that the decision to change the antiretroviral regimen requires consideration of such factors as HIV RNA and CD4 levels and the changes in these measurements, the remaining treatment options in terms of potency, potential resistance patterns from previous antiretroviral therapy and the possibility of side effects, drug interactions, dietary requirements and the need to alter concomitant medications. According to the guidelines, the need to change therapy may arise in three different situations: (1) incomplete suppression of the viral load despite potent antiretroviral therapy, (2) a return of detectable HIV RNA after having achieved undetectable viremia with potent antiretroviral therapy and (3) persistently detectable viremia despite potent combination antiretroviral therapy.

The guidelines specify criteria that should prompt consideration for instituting a change in the antiretroviral regimen, as follows:

  • Less than a 0.5 to 0.75 log reduction in plasma HIV RNA by four weeks after initiation of therapy, or less than a 1 log reduction by eight weeks.

  • Failure to suppress plasma HIV RNA to undetectable levels within four to six months of initiating therapy.

  • Detection of virus in plasma after initial suppression to undetectable levels, suggesting the development of resistance.

  • Any reproducible significant increase, defined as threefold or greater, from the nadir of plasma HIV RNA not attributable to intercurrent infection, vaccination or testing method except as noted above.

  • Undetectable viremia in the patient receiving two NRTIs. The guidelines state that patients who are receiving two NRTIs and have no detectable virus have the option of continuing to receive the two-NRTI regimen or modifying the regimen to conform with a strongly recommended regimen. The guidelines note that the frequency of virologic failure is substantially higher in patients receiving two NRTIs as opposed to those receiving any one of the regimens that are in the strongly recommended category.

  • Persistently declining CD4 counts as measured on at least two separate occasions.

  • Clinical deterioration.

Therapeutic options in the antiretroviral regimen depend on the indication for the change. For example, if viremia has dropped to undetectable levels but drug intolerance or toxicity has developed, the offending drug preferably should be replaced with an agent in the same class with a different toxicity or tolerance profile. If viral suppression has been induced but the patient is not receiving a strongly recommended regimen, the current regimen can be continued or changed so that it constitutes a preferred regimen.

The guidelines note that there are few data with which to make a recommendation for how to change therapy in patients in whom a strongly recommended regimen has failed in maintaining viral suppression. Evidence suggests that resistance to one protease inhibitor or NRTI often signals reduced susceptibility to other drugs in these classes.

Antiretroviral Therapy in Adolescents

According to the guidelines, the dosages for drugs used to treat HIV and opportunistic infections in adolescents should be based on the adolescent's stage of puberty, not on chronologic age. Dosages for adolescents in early puberty (Tanner stages I and II) should be in the pediatric range. In late puberty (Tanner stage V), dosages should be given according to recommended dosages for adults. The guidelines stipulate that close monitoring for drug efficacy and toxicity should be performed, especially in adolescents who are in a growth spurt (i.e., Tanner stage III in females and Tanner stage IV in males).

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