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Clinical studies performed in the 1980s and early 90s focused on monotherapy, or use of one antiretroviral drug at a time, and following patients through to clinical endpoints, such as opportunistic illness or death. The earliest studies found that patients with AIDS experienced some survival benefit and reduced number of opportunistic illnesses on zidovudine vs. AIDS patients on placebo. However, clinical benefit was limited in groups of patients who started zidovudine earlier in the course of infection.
Later clinical studies began testing combinations of two or more drugs against other combinations, as well as against monotherapy. Some began to use laboratory markers, such as decline in CD4 count or increases in virus burden, instead of clinical endpoints to measure a regimen's effectiveness. Although many studies continue to use clinical and survival endpoints, the use of these markers allows drug trials to be completed more rapidly.
The number of antiretroviral drugs approved by the US FDA has increased dramatically in the past three years, and continues to grow. Research on the clinical efficacy of numerous possible combinations will take years to collect and evaluate, while clinicians are faced with situations that cannot wait for these future findings. The following general recommendations are those of expert HIV researchers and clinicians, based on current data and new understandings about viral activity. Following is a brief summary of the main points from the Report of the NIH Panel to Define Principles of Therapy of HIV Infection:
Ongoing HIV replication leads to immune system damage and progression to AIDS. HIV infection is always harmful, and true long-term survival without significant immune impairment is unusual.
Plasma HIV RNA levels indicate the magnitude of HIV replication and the speed of CD4+ cell destruction, while CD4+ cell counts indicate how much HIV-induced immune damage has already happened. Plasma HIV RNA levels and CD4+ cell counts must be measured at regular intervals to determine the risk of disease progression and to decide when to start or change antiretroviral regimens.
Because risk of disease progression differs among individuals, treatment decisions should be individualized by plasma HIV RNA levels and CD4+ T-cell counts.
To stop the virus from mutating into drug-resistant forms, its replication must be completely suppressed. Since HIV RNA tests cannot detect very low levels of viral production, an undetectable HIV RNA on the current test does not necessarily mean that the viral growth is completely suppressed. Regardless of these limitations on antiretroviral drugs and HIV RNA test technology, maximum achievable suppression of HIV growth should be the goal of therapy.
The most effective way to suppress HIV replication over the long term is to start the patient on a combination of effective anti-HIV drugs with which the patient has not previously received, and that are not cross-resistant with other antiretrovirals the patient has taken before.
Each of the antiretroviral drugs used in combination therapy regimens should always be taken according to optimum schedules and dosages, and under the conditions specified for maximal drug absorption.
The available antiretroviral drugs are limited in number and mechanism of action, and cross-resistance between specific drugs has been documented. Therefore, any change in antiretroviral therapy increases limitations on future treatment options.
Women should receive optimal antiretroviral therapy regardless of pregnancy status.
The same principles of antiretroviral therapy apply to both HIV-infected children and adults, although the treatment of HIV-infected children involves unique pharmacologic, virologic, and immunologic considerations.
Persons with acute primary HIV infection should be treated with combination antiretroviral therapy to suppress viral replication to levels below the limit of detection of plasma HIV RNA assays.
HIV-infected persons, even those with viral loads below detectable limits, should be considered infectious and should be counseled to avoid sexual and drug-use behaviors that are associated with transmitting or acquiring HIV and other infections.
Drug combinations that include only reverse
transcriptase inhibitors (RTIs) generally will not reduce virus level as effectively as a
combination that includes both RTIs and a protease inhibitor (PI). The only way to verify
effectiveness in any individual patient, however, is to check virus levels before and
after starting a regimen, since individual responses vary widely.
Limitations on antiretroviral therapy
No "average patient" exists. Some patients will do better and some will do worse than what clinical studies would predict. Health care providers must work with each patient to develop a treatment strategy that is both clinically sound and appropriate for that individual's needs, priorities, and circumstances of daily life. Not all patients will be able to tolerate all drugs, and the patient's understanding, readiness to commit to the regimen, and history of adherence to previous regimens must be considered in choosing them appropriately.
Optimal time to start antiretroviral therapy in an HIV-infected adult is still uncertain. The asymptomatic stable patient presents the most difficult challenge, and several factors must be weighed prior to making a decision:
willingness of the individual to begin therapy;
degree of existing immunodeficiency as reflected in the CD4 count;
risk of disease progression, as determined by the HIV RNA level;
potential risks and benefits of antiretroviral drugs; and
the likelihood of adherence to the prescribed regimen.
In some circumstances, the timing of antiretroviral therapy may depend partly on drug availability. The regimen should not be started until it is assured that the all of the drugs in the regimen will be available to the patient.
Antiretroviral therapy is recommended for patients with any of the following:
high virus burden regardless of CD4 count. The 1997 NIH panel recommends that if using RT-PCR viral load assay, start treatment about >20,000 copies/ml. The panel acknowledges that recommendations for therapy cannot be based on any absolute number, with our current limitations on test sensitivity, therapy and data from clinical trials. (See viral burden protocol.)
CD4 count <500 (though some providers might consider deferring tx if stable CD4 count >350, with HIV RNA titers between 5,000-10,000 and no symptoms)
rapidly declining CD4 count (>300 CD4 loss over a 12 to 18 month period), at any HIV RNA level
symptomatic disease (oral thrush, hairy leukoplakia, wt loss, fevers, night sweats), at any HIV RNA level or CD4 count
acute or primary HIV infection if unable to enroll in a clinical trial
Therapy should be considered in any patient with detectable HIV RNA who are willing to commit to a difficult drug regimen and the necessary medical follow-up.
Start any drug regimen after a thorough patient history and labwork to rule out pre-existing abnormalities (e.g., history of pancreatitis, nephrolithiasis, or peripheral neuropathy; current anemia, leukopenia, etc.) which may worsen due to that drug's toxicity. Before starting the regimen, it is also necessary to have a detailed discussion with the patient about his or her commitment to a difficult, potentially toxic medication regimen and returning for the required follow-up. The patient must also understand that the first treatment regimen is the best opportunity for effective viral suppression, which is the primary goal of antiretroviral treatment. Numerous strategies are being tested for effectiveness in supporting patient adherence to the regimen. Extensive patient education, telephone contacts of office staff who can answer questions about side effects or difficulties, family meetings and peer support are used in some settings. Rapport and accessibility appear to be important predictors of adherence, and some offices see the patient for two or three appointments prior to starting antiretrovirals. Patients may also be given "test regimens" for a few weeks using inactive pills, to help understand how the medicine schedule may fit into his or her life, before starting the actual drugs.
If starting a regimen which is likely to worsen existing pathology, close monitoring is essential. Baseline and follow-up labwork should include plasma HIV RNA levels, since this indirectly reflects the number of productively infected cells in the body, and is considered the best predictor of disease progression. The FDA-approved Amplicor HIV-1 MonitorÔ (Roche) reportedly detects HIV RNA levels between 400 and 750,000 copies/mL. The choice to accept or decline antiretroviral therapy ultimately lies with the patient. Whether or not the patient accepts antiretroviral drugs, monitoring, preventive care, and other types of medical treatment should be provided. Changes in lab results and patient condition should be used as opportunities to reassess the patient's wishes for antiretroviral treatment, and educate her/him about new medications and research findings. Appropriate antiretrovirals should be re-discussed and offered at regular intervals, even to patients who initially refuse such treatment.
For effective starting regimens for patients with no prior therapy, choose one pair from Column A and one from Column B:
| Column A | Column B |
| · zidovudine + didanosine* | indinavir |
| · zidovudine + zalcitabine | nelfinavir |
| · zidovudine + lamivudine | saquinavir soft gel |
| · didanosine + stavudine | ritonavir |
| · stavudine + lamivudine | ritonavir + saquinavir (either formula) |
*hydroxyurea is added by some experts to ddI-containing regimens to increase its potency.
Alternative treatment, less likely to provide sustained viral
suppression:
NNRTI + 2 NRTIs (from column B above)
Note: Patients who are poor candidates for
three-drug regimens may do well on regimens of two NRTIs that develop resistance slowly.
Although a sub-optimal regimen, if viral load can be reduced even by 1 or 2 logs, it will
help decrease opportunistic illnesses and prolong life. It will also help avoid
development of resistance to the protease inhibitor class, and preserve if for future use
when the client may be more ready or able to adhere to a complex three-drug regimen.
Special note on protease inhibitors
Protease inhibitors should not be given alone, intermittently, or in lower doses than recommended due to potential for rapid development of resistance. Patients must take the full dose on schedule, and not take "days off" from such regimens. Careful medication dosing is especially important, since viral resistance to one protease inhibitor may transfer to other protease inhibitors. This greatly limits options for future therapy. Resistant viral strains, once developed, may also be transmitted to other people through risky behavior.
Follow-up: Check plasma HIV RNA 3-4 weeks after starting new regimen and then along with the CD4 counts to detect signs of regimen failure. Plasma RNA level should decrease at least 1/2 log from baseline; that is, the level should be less than 1/3 of its pre-treatment value. More effective regimens reduce virus levels to <1/10 of baseline; the optimal combination prevents future viral resistance by stopping viral replication altogether. Unfortunately, current HIV RNA test technology is relatively insensitive, and can only detect viral levels down to about 400 copies/ml. More sensitive tests are in development and are expected to be approved in the near future.
Patients with very high baseline viral loads may take longer to show
the full effect from an effective regimen. A patient with a virus load that has declined
significantly at 4 weeks should be re-checked at 16 weeks, to quantitate maximal effect.
Some studies have suggested that a few of these patients may take up to 6 months to see
maximal reduction in virus loads. Such patients are also less likely to achieve
undetectable viral loads than patients with low baseline virus levels.
Antiretroviral regimens should be changed in the event of intolerance, non-adherence, or failure. Failure can be defined as:
lack of initial response in viral burden test, or <1/2 to 3/4 log decrease 4 weeks after start of regimen
viral burden decreases < 1 log (less than tenfold) by 8 weeks
viral burden does not go below level of detection by 4-6 months--although must consider that, given limited options, partial viral suppression is better than none at all. Some clinicians would observe carefully, but delay changing the regimen if a patient achieved substantial reduction (1.5-2 logs) from baseline.
any substantial increase in virus burden from its initial decrease, if not due to infection, vaccination, or problem with test methodology--although some clinicians would postpone changing until level had climbed above 10,000 copies/ml
clinical disease progression, although a new opportunistic illness in the presence of pre-existing severe immunosuppression may not reflect a failure of antiretroviral therapy, especially in the presence of a good virologic response
rapidly or persistently declining CD4 counts
A final consideration in deciding whether or when to change therapies is the limited choice of available agents, which may further reduce future treatment options for the patient. It is necessary to balance partial suppression with the likelihood of future resistance. Consultation with an experienced HIV provider is appropriate when considering changes in therapy.
Because of the likelihood of viral resistance to all the drugs in a regimen that has failed, try to change all the drugs in the regimen. If that is not possible, at least change two of the medications. Do not add a single drug to a failing or inadequate regimen, since that is likely to have the effect of serial monotherapy. If resistance to the previous drugs is already present, resistance to the added drug is only a matter of time. Recent evidence suggests that broad cross-resistance exists among the PIs, and viral strains that are resistant to one of them will have reduced susceptibility to most or all the other PIs. Cross-resistance between indinavir and ritonavir is almost complete, and although information about nelfinavir is less available, some degree of cross-resistance between nelfinavir and ritonavir or indinavir may exist. Because of this, when changing from a 2 NRTI/1 PI combination, the likelihood of success is decreased even if the new regimen has 2 new NRTIs and a new PI. Some experts add two new PIs in the subsequent regimen, or switch to a regimen containing 2 NRTIs and an NNRTI. Note that dosage modification is often required due to drug interactions (see table at end of this section) When changing regimens, always consider which drugs foster cross-resistance to others in the same class.
Here are some additional guidelines from NIH for changing an antiretroviral regimen for suspected drug failure:
When the decision to change therapy is based on viral load, it is preferable to confirm with a second viral load.
Distinguish between the need to change a regimen due to drug intolerance or inability to comply with the regimen versus failure to achieve the goal of sustained viral suppression; single agents can be changed in the event of intolerance.
In general, do not change a single drug or add a single drug to a failing regimen; it is important to use at least two new drugs and preferably to use and entirely new regimen with at least three new drugs.
Many patients have limited options for new regimens of desired potency; in some of these cases it is rational to continue the prior regimen if partial viral suppression was achieved.
In some cases, regimens identified as sub-optimal for initial therapy are rational due to limitations imposed by toxicity, intolerance or non-adherence, especially in late-stage disease. For patients with no rational alternative options who have virologic failure with return of viral load to baseline and a declining CD4 count, there should be consideration for discontinuing antiretroviral therapy.
Experience is limited with combinations of two protease inhibitors or combinations of PIs with nevirapine or delavirdine; for patients with limited options due to drug intolerance or suspected resistance these regimens provide possible alternative treatment options.
Avoid changing from ritonavir to indinavir or vice versa for drug failure, since high-level cross resistance is likely.
Avoid changing from nevirapine to delavirdine or vice versa for drug failure, since high-level cross resistance is likely.
There is limited information about the value of restarting a drug that the patient has previously received. The experience with zidovudine is that resistant strains are often replaced in the blood with "wild-type" zidovudine-sensitive strains once zidovudine is discontinued, but resistance recurs rapidly if zidovudine is restarted. Although this has not yet documented with other drugs, the conservative position is that the same thing will happen.
The decision to change therapy and the choice of a new regimen requires that the clinician have considerable expertise in the care of people with HIV. Those less experienced in the care of persons with HIV are strongly encouraged to obtain assistance through consultation with or referral to a clinician with considerable expertise in the care of people with HIV.
Examples of potential combinations to start after failure of initial regimen:
| Initial Regimen | Subsequent options |
| zidovudine-lamivudine-protease inhibitor1 | stavudine-didanosine-protease inhibitor2 (or above with 2 protease inhibitors) stavudine-didanosine-NNRTI |
| stavudine-lamivudine-protease inhibitor1 | zidovudine-didanosine-protease inhibitor2 zidovudine-didanosine-NNRTI ritonavir-saquinavir-NRTI |
| zidovudine-didanosine-protease inhibitor1 | stavudine-lamivudine-protease inhibitor2 stavudine-lamivudine-NNRTI ritonavir-saquinavir-NRTI |
| stavudine-didanosine-protease inhibitor1 | zidovudine-lamivudine-protease inhibitor2 zidovudine-lamivudine-NNRTI ritonavir-saquinavir-NRTI |
| zidovudine-didanosine-NNRTI | stavudine-lamivudine-protease inhibitor1 |
| zidovudine-lamivudine-protease inhibitor1 |
*Zidovudine alone is considered suboptimal therapy. Patients on any
monotherapy should be re-evaluated.
Additional notes on failed regimens:
In patients with advanced disease or those with extensive zidovudine experience, new combinations of nucleoside analogues plus a protease inhibitor are appropriate. In patients who have received a combination of two nucleoside analogues, a change to combination therapy with at least two new drugs, such as 2 nucleoside analogues and a protease inhibitor, may be appropriate.
NRTI combinations to avoid due to virologic problems or overlapping toxicities are:
stavudine + zalcitabine (neuropathy)
didanosine + zalcitabine (pancreatitis)
stavudine + zidovudine (antagonistism)
zalcitabine + lamivudine
If a regimen is changed due to toxicity or intolerance, it is not necessary to change the complete regimen. If necessary to stop one drug, either stop all drugs and resume when the substitute drug is available, or substitute for a new drug from the same class or category as soon as the offending drug is discontinued.
Please note that many of the antiretroviral drugs interact with other common medications, and when starting or changing a regimen, review all the patient's current medications. (See individual medications listed in this section for more complete information on drug interactions.) For further reference, updated interaction information, authored by Charles Flexner, MD, and Stephen C. Piscitelli, Pharm.D., is available from Health Communication Group's internet site at http://www.healthcg.com
Antiretroviral therapy during acute or primary HIV infection
Patients with acute HIV infection may experience symptoms such as rash, fever, lymphadenopathy, fatigue, weight loss, nausea and headache, but still be negative or indeterminate on the HIV antibody test. If a careful HIV risk history reveals the patient to be a significant risk for HIV infection, an HIV RNA test can be performed to ascertain whether or not there is viremia. Although optimal therapy in this group of patients is unknown, combinations of agents that are most likely to maximally suppress viral replication (such as two RTIs and a protease inhibitor) are recommended. The patient must be carefully counseled regarding potential limitations, such as toxicity, pill burden, cost, and the possible development of drug resistance before starting on an antiretroviral regimen. These patients should be maintained with the same kind of follow-up of viral load and CD4 count as patients with established infection. Patients in whom the initial HIV antibody test was negative, with a positive P-24 or HIV RNA, should be re-tested within 3-4 weeks to fully document the diagnosis of HIV infection.
Pregnant women: ZDV is the recommended antiretroviral for use to reduce risk of vertical transmission, but is suboptimal therapy for treating the woman's infection. For women intolerant of ZDV, enroll in a clinical trial of ddI or other regimen under study for reducing vertical HIV transmission (1-800-TRIALS-A). Note that the Principles of Treatment of HIV Infection, published in 1997 by the NIH, state that women with HIV infection should receive optimal antiretroviral therapy regardless of pregnancy status. See protocols: Reducing Maternal-Infant HIV Transmission and Treatment during Pregnancy.
Occupational exposure to HIV (percutaneous exposure to blood or
other potentially infectious fluid): See MMWR 1996;45:468-472 for guidelines on
post-exposure prophylaxis (PEP). For twenty-four-hour expert consultation on choosing
appropriate drugs for PEP, call 1-888-HIV-4911. Each institution should have its own
policy, procedures, and antiretroviral drug kit so that PEP can begin without delay.
New antiretroviral drugs are still in development, and new combinations
are being tested all the time. As of early 1998, an old drug, hydroxyurea, is being
considered in the treatment of HIV infection. This drug is being tested alongside newer
ones in combination regimens, and many clinicians are using it with other antiretrovirals
in their clients with limited options. Studies are also continuing on newly-infected
patients to determine if HIV reproduction can be completely suppressed in the body long
enough that it completely dies out.
All drugs have toxicities, and the patient must be informed about what to watch for and expect. She/he must know what measures to take for reactions and side effects, e.g., keep taking zidovudine in the presence of mild nausea but discontinue ddI and seek medical attention if severe abdominal pain occurs.
Be sure the patient knows whether to take each drug on an empty or full stomach, if applicable, and how to space it between other drugs which may prevent its absorption (see individual drug information). For example, patients on indinavir must take it on an empty stomach or with a very small, low-fat meal, and should not drink grapefruit juice with indinavir, because either will reduce drug levels. Saquinavir, by contrast, is best absorbed when taken with a high-fat meal; and grapefruit juice increases saquinavir levels.
Ritonavir must be refrigerated, and cannot be subjected to high humidity for more than a day or so. It may be taken out of the refrigerator up to 24 hours before use, but may not be kept in pockets (body heat), or in automobiles where the sun will heat it. Be sure the patient has facilities and understands the need for this.
Antiretroviral drugs require a commitment to use. There are limited numbers of such drugs available, and if they are taken incorrectly, your virus can quickly become resistant to the medication. This will mean even fewer choices, and probably less effective treatment, later on. (Review the actual regimen with the client, integrating times for each dose with client's mealtimes--or between them, as appropriate--and be sure it is possible for the client at these times.)
Safer sex recommendations must be followed, and other high-risk
activities (needle sharing, etc.) must be carefully avoided, even with infected partners.
If the viruses in your body develop resistance to some of these medications, and you pass
those viruses on to another person, she/he will not be able to effectively use those
medications either.
1) Manufacturers' product labeling.
2) USDHHS. Guidelines for Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Federal Register, 1997.
3) USDHHS and the Henry J. Kaiser Foundation. Report of the NIH Panel to define principles of therapy of HIV infection. Federal Register, 1997.
4) Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral Therapy for HIV infection in 1997: Updated Recommendations of the International AIDS Society - USA Panel. JAMA 1997;277:1962-1969.
5) Cotton D. The use of protease inhibitors. AIDS Clinical Care, 1996, 8(5):37-41.
The following section is intended for brief review of common medications used in HIV and AIDS care, and their primary usages in the HIV-infected population.
Brief information on pregnancy categories has been added to medications listed in this section. Even though this data is almost always much less than clinicians need to know, it tells what testing has been performed on animals during gestation, which is of some utility in determining the medication's possible effect on human fetal development. Interestingly, animal teratogenicity does not necessarily mean that a drug is teratogenic in humans; out of 1200 known animal teratogens, only about 30 are known to be teratogenic in humans (USPHS, 1997). Because of a few serious incidents with prescription drugs causing birth defects, drug companies are reluctant to perform clinical trials on pregnant women. Some drug companies have set up a confidential registry to help collect data on the fetal effects of antiretroviral exposure in utero, to try and help fill in the gaps on what clinicians need to know to care for pregnant women. Clinicians are encouraged to use this service, and help contribute information on the antiretroviral drugs (see pregnancy protocols). This effort will eventually help clinicians, but much more is needed. While we await these observations, the clinician must offer treatment to pregnant women despite limited information on possible fetal effects.
Before using any drug during pregnancy, refer to full prescribing information available on the drug. The protocol, Treatment of the HIV-Infected woman during pregnancy, sets forth more guidelines on determining how drugs should and should not be used during gestation.
The following Pregnancy Category codes are used in this section:
Category A - Adequate, well-controlled studies in pregnant women have failed to show fetal risk.
Category B - No evidence of risk in humans. Either animal findings show risk, but human findings do not; or no adequate human studies have been done, and animal studies show no risk.
Category C - risk to fetus cannot be ruled out. Human studies are lacking, and animal studies either haven't been done, or are positive for fetal risk. Consider use if benefit outweighs potential risk.
Category D - Possible evidence of risk. Investigational or post-marketing data show risk to the fetus. However, potential benefits may outweigh the potential risk. Generally this rating is reserved for drugs with no safer alternatives.
Category X - Contraindicated in pregnancy. Studies have shown fetal risk clearly outweighs any possible benefit to the patient.
NOTE: The following drug list and information is neither comprehensive nor all-inclusive. This information is not intended to supplant detailed review of labeling and packaging materials, particularly for side effects and additional drug interactions.