Author: Susa Coffey, MD
Potent combination antiretroviral therapy (ART), typically consisting of three or more antiretroviral (ARV) drugs, has greatly improved the health and survival rates of HIV-infected patients in areas of the world with access to ARVs. More than 20 individual ARVs in six classes are available in the United States, in addition to several fixed-dose combination preparations. These can be combined to construct a number of effective regimens for initial and subsequent therapy. Although ART has its limitations (see below), it saves lives and improves immune system function, reduces the risk of many HIV-related and "non-AIDS" complications, and reduces the risk of HIV transmission. Increasingly, several lines of evidence point to the benefit of ART even for patients with high CD4 counts.
Mortality and morbidity benefits of ART are particularly obvious in patients with relatively advanced immune suppression or with symptoms related to HIV infection. For asymptomatic patients with higher CD4 counts (e.g., >350 cells/µL), the question of when to initiate ART remains an area of research and debate. It is clear there is a spectrum of risk for adverse outcomes that increases as the CD4 count declines. In persons with CD4 counts of <200 cells/µL, effective ART dramatically decreases morbidity and mortality. For persons with CD4 counts of 200-350 cells/µL, data from randomized controlled studies as well as cohort studies also demonstrate a reduction in both AIDS and non-AIDS events among those who start ART. Although it is not clearly known at what CD4 threshold ≥350 cells/µL therapy should be started, a variety of data from observational cohort studies show a reduction in death as well as in AIDS and non-AIDS related complications among persons who start ART with CD4 counts of >350 cells/µL rather than <350 cells/µL. It should be noted, however, that these findings are not consistent across all studies. For patients with CD4 counts of >500 cells/µL, the limited data that are currently available (from cohort studies) are inconsistent on the question of whether initiation of ART results in better outcomes. A randomized clinical trial of earlier (>500 cells/µL) versus deferred (<350 cells/µL) treatment is under way, and the results of that study along with those from the cohort studies may help define an optimal threshold at which to initiate ART.
Meanwhile, in recent years, a growing body of evidence has demonstrated adverse effects of untreated HIV on many organ systems and aspects of functioning, even in persons with high or relatively high CD4 counts (>350-500 cells/µL). These include the following:
Many of these effects appear to be mediated through persistent immune system activation and ongoing inflammation in various organ systems. ART with virologic suppression appears to reduce immune activation and protect against many of these morbidities, but it may not restore immune system function to normal and may not fully reverse disease processes. The beneficial effects of ART may be attenuated for patients who start ART with lower CD4 cell counts. Additionally, the risk of certain ARV-related adverse events may be greater for those who start ART at lower CD4 levels.
Although ART can confer substantial health benefits, it has significant limitations. ART does not cure HIV infection and it requires that multiple medications be taken for life (i.e., potentially many decades). It may cause a variety of adverse effects (some severe), is expensive, requires close adherence to be effective and to prevent the emergence of resistance, and sometimes fails (because of the patient's imperfect adherence or other factors). The failure of an ARV regimen when accompanied by drug resistance usually means that subsequent regimens are less likely to succeed.
In past years, many of the available ARVs presented challenges in the realms of adverse effects, pill quantity, dosing frequency, and durability. Given these limitations of ART, much attention was devoted to estimating the point at which the potential benefits of ART outweighed the potential risks of ART. Today, the newer ARV regimens, specifically those currently recommended by the U.S. Department of Health and Human Services (DHHS) for initial therapy, are for most patients, simple, tolerable, and effective. As a result of both the availability of ARV regimens that are less toxic and easier to administer, and the increasing appreciation of the adverse impacts of untreated HIV, the tipping point between the potential benefit and the potential risk of ART is shifting. Most HIV experts (as is reflected in the current DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents; see below) recommend earlier initiation of treatment, and many recommend ART for all willing individuals regardless of CD4 count, unless there are compelling reasons not to treat (see "When to Initiate Therapy: DHHS ARV Guidelines," below; also see the DHHS Guidelines for a full discussion of these issues). An expected additional benefit of earlier treatment is the likelihood that HIV transmission will be reduced.
Of course, in deciding when to start ART for the individual patient, practitioners must weigh the expected benefits of ART for that person (in terms of morbidity and mortality) against the possible risks of ART (e.g., toxicity, drug resistance, adverse drug interactions).
Although implementing and monitoring ART is complex, a number of guidelines from expert panels are available to help clinicians select effective regimens for particular patients. The DHHS keeps a repository of frequently updated recommendations on the use of ARV medications for adults and adolescents, pregnant women, and children. All clinicians who treat HIV-infected patients should be familiar with the most current versions of these treatment guidelines. They are available on the Internet at the AIDSinfo website. The DHHS Guidelines are referenced frequently in this chapter.
The following recommendations have been adapted from the DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.
|AIDS-defining illness||Strongly recommended|
|CD4 count <350 cells/µL||Strongly recommended|
|CD4 count 350-500 cells/µL||Strongly recommended by 55% of the panel, moderately recommended by 45% (more urgent at lower CD4 levels)|
|CD4 count >500 cells/µL||Moderately recommended by 50% of the panel treatment, considered optional by 50%|
Persons with certain conditions should be treated with ART regardless of CD4 count. These conditions include the following:
In some situations, ART may be needed relatively urgently. These include the following:
(Adapted from U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents; Table 2a, Conditions Favoring More Rapid Initiation of Therapy. January 10, 2011.)
Obtain the patient's history and review of systems, including the following (see chapter Initial History):
Perform the following objective tests:
Make the following basic decisions:
After educating the patient about the purpose and logistics of the proposed regimen and assessing the patient's potential for adherence, ART can be initiated, changed, or postponed accordingly.
The primary goal of therapy is to reduce HIV-related morbidity and mortality through maximal and durable viral suppression; this includes improving immune function and reducing HIV-associated inflammation. Among the secondary goals are improving quality of life and reducing the risk of HIV transmission.
No "average patient" exists. Some patients will do better during treatment and some will do worse than 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. Despite the fact that the regimens currently recommended by the DHHS Guidelines are more compact and have fewer adverse effects than earlier regimens, not all patients will be able to take or tolerate all drugs, and the patient's understanding, readiness to commit to the regimen, and history of adherence to previous regimens must be considered when choosing ARV combinations. Major considerations are as follows:
Of course, the patient's willingness to begin ART is critical, as mentioned above. Patients have the right to decline or postpone ART. This decision should not affect any other aspect of care, and ART should be offered again at each visit to patients for whom treatment is indicated. If mental health issues, addiction, or the patient's social situation are barriers to adherence, initiate appropriate referrals and reassess adherence barriers at regular intervals.
Before starting ART, it is important to have a detailed discussion with patients about their readiness to commit to a medication regimen, the expected benefits and possible adverse effects, and required monitoring and follow-up visits. Patients must understand that the first treatment regimen offers the best opportunity for effective viral suppression and immune reconstitution, which are the primary goals of ART.
Numerous strategies have been tested for their effectiveness in supporting patients' adherence to the ART regimen. Successful approaches include extensive patient education, telephone contact with office staff members who can answer questions about adverse effects or other difficulties, family meetings, and peer support. Trust and accessibility appear to be important predictors of adherence, and some practitioners see the patient for two or three appointments before starting ART.
Compact regimens consisting of fewer pills and once-daily dosing often encourage adherence. Advise patients about potential adverse effects and at the same time let them know that many adverse effects may be treated or that substitutions often can be made for problematic ARVs. The choice to accept or decline ART ultimately lies with the patient (see chapter Adherence).
Choosing an initial regimen that fits the patient's lifestyle and that is likely to be tolerable, and easy to take, will improve the likelihood of long-term success with that regimen. If patients develop toxicities to one or more components of an initial regimen, substitutions typically can be made without limiting the success of the regimen. Close monitoring and "check-in" appointments allow these adjustments to be made under clinical supervision. Close monitoring also can help to identify medication toxicities that may limit treatment and to detect early signs of inadequate medication adherence; early intervention to treat adverse effects and to support adherence may increase the likelihood of treatment success.
Regimens should be selected with consideration of both patient factors and medication factors. The patient's schedule, adherence history, and self-defined goals of ART should be considered in selecting a regimen to which the patient will best adhere. The patient's comorbid conditions and potentially interacting medications should be evaluated for possible contraindications or synergism. The ARV history and all resistance profiles should be reviewed carefully so that a regimen that will be likely to achieve durable viral suppression can be chosen. The CD4 cell count should be reviewed if nevirapine is being considered, and viral tropism and the HLA-B*5701 status should be determined if maraviroc or abacavir, respectively, is being considered. The patient's HBV status will influence selection of NRTIs (tenofovir + emtricitabine or lamivudine should be included in the ART regimen, for co-treatment of HIV and HBV, unless contraindicated). In women who are pregnant or likely to become pregnant, ARV pregnancy categories and ARV teratogenicity should be taken into account. Drug interactions amongst ARVs or between ARVs and other medications should be evaluated, as dosage adjustments may be required or certain combinations may be contraindicated (see Tables 14, 15a-e, and 16a-b of the DHHS Guidelines).
The advantages and disadvantages of various drug classes and individual drugs recommended for use in initial therapy are reviewed in Table 6 of the DHHS Guidelines.
For initial therapy in patients with wild-type HIV virus, the DHHS Guidelines recommend the use of two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with either a nonnucleoside reverse transcriptase inhibitor (NNRTI), a ritonavir-boosted protease inhibitor (PI), or an integrase inhibitor (II). Drug combinations that include only NRTIs generally do not reduce virus levels as effectively as two-class combinations. The question of whether to use an NNRTI, a PI, or an II in initial therapy is a matter of debate. Some clinicians advocate using an NNRTI or II initially to preserve use of the PI class for later and to avoid PI-related toxicities. Others are more concerned about the potential toxicities of NNRTIs or the low genetic barrier to resistance presented by NNRTIs and IIs, and instead recommend starting with a PI-containing regimen. Each of the initial regimens proposed by the DHHS Guidelines is highly effective if taken as directed, and each has specific advantages and disadvantages (see Table 6 of the DHHS Guidelines). In the end, the regimen should be selected with the individual patient in mind because the only effective combination for that patient is the one that he or she is willing and able to take on a consistent basis. See the information on drug resistance and toxicities below as well as the full text of the DHHS Guidelines for more complete discussions.
Salvage therapy for patients with ARV-resistant HIV often comprises agents from three or more ARV classes; consult with an expert.
Ritonavir is used at low doses in combination with most other PIs to enhance or "boost" the serum level and prolong the half-life of the PI. This strategy generally decreases the dosing frequency and the number of pills required, and it improves the activity of some PIs. Several currently used PIs require boosting with ritonavir, and some require ritonavir boosting to overcome certain interactions between PIs and other medications (e.g., atazanavir must be boosted with ritonavir if tenofovir also is a component of the ARV regimen); see Drug Interactions, below, and Tables 13, 14, and 15 in the DHHS Guidelines.
More than 20 ARVs in six drug classes have been approved for use in the United States by the U.S. Food and Drug Administration (FDA) (see Appendix B, Tables 1-6 and Tables 11-13 in the DHHS Guidelines). In recent years, an increasing number of fixed-dose combinations (FDCs) have become available to simplify dosing and reduce pill burden.
These include four NRTI combinations:
One PI coformulation:
And a one-pill-per-day formulation of two NRTIs and one NNRTI:
Other FDCs are in development and may become available in coming years.
The DHHS Guidelines suggest "preferred" and "alternative" components for initial therapy (Table 1). Clinicians should note that these recommendations change over time as new data regarding efficacy or toxicity become available. Among regimens with adequate potency (taking into account possible ARV resistance), regimen selection should be guided by factors such as anticipated tolerability, pill burden, drug interactions, and the patient's comorbid conditions. Other agents or combinations may be appropriate or preferable for individual patients (see Table 5a of the DHHS Guidelines).
|NNRTI based||Efavirenz1 + tenofovir/emtricitabine (TDF/3TC)2|
|PI based||Atazanavir/r + TDF/FTC2|
Darunavir/r (once daily) + TDF/FTC2
|II based||Raltegravir + TDF/FTC2|
|Pregnant women||Lopinavir/r (twice daily) + zidovudine (ZDV)/lamivudine (3TC)2|
|NRTI based||Efavirenz1 + (abacavir [ABC]/3TC)2,3 or (ZDV/3TC)2|
Nevirapine4 + ZDV/3TC2
|PI based||Atazanavir/r + (ABC/3TC)2,3 or (ZDV/3TC)2|
Fosamprenavir/r (once daily or twice daily) + (ABC/3TC)2,3 or (ZDV/3TC)2 or (TDF/FTC)2
Lopinavir/r (once daily or twice daily) + (ABC/3TC)2,3 or (ZDV/3TC)2 or (TDF/FTC)2
Note: The DHHS Guidelines also list regimens that "May Be Acceptable" and "Should Be Used with Caution," see Table 5b in the DHHS Guidelines.
The use of convenient and simplified dosing is an obvious strategy for improving adherence, particularly with the availability of coformulations that reduce pill burden (see "Preferred Starting Regimens," above). The DHHS Guidelines currently include three once-daily combinations among "preferred" regimens for initial therapy, and list several other possibilities among "alternative" regimens.
ARV medications never should be given as single agents, in two-drug regimens, in suboptimal regimens, or in lower dosages than recommended, because of the potential for development of resistance. High-level resistance to NNRTIs, as well as to emtricitabine and lamivudine, may develop quickly (i.e., within days to weeks) in these situations, and the same may be true for the II raltegravir. It may take longer for high-level resistance to develop to other NRTIs and to ritonavir-boosted PIs. Patients must be instructed to take the full dosage of all medications on schedule and to avoid skipping doses or taking "days off" from their regimens. Careful medication dosing is important because resistance to one drug within a particular class may transfer to other drugs in the same class (cross-resistance). Cross-resistance can limit the options for future therapy significantly or necessitate the use of very complicated regimens in the future. Once resistant viral strains have developed, they may be transmitted to other people.
Acquired or "primary" resistance, in which a patient is infected with ARV-resistant virus, is common in parts of the United States. Because both multi- and single-class resistance has been found among ARV-naive persons in many U.S. cities, it is recommended that individuals with newly diagnosed HIV infection and all others entering care should receive a baseline resistance test. This test should be obtained as early as possible, in order to maximize the likelihood of detecting transmitted mutations, and before initiation of ART (see chapter Resistance Testing).
Many of the ARVs interact with one another as well as with other common medications. When starting or changing an ARV regimen, review all the patient's current medications carefully for possible drug interactions. See chapter Drug-Drug Interactions with HIV-Related Medications for a summary of this issue and for references and resources to review medication lists and combinations. For further information on drug interactions involving ARVs, see Tables 15a-e and 16a-b in the DHHS Guidelines.
Most clinicians in the United States avoid using the NRTIs zidovudine (except for pregnant women), stavudine, or didanosine if other options are available, because of the high rates of metabolic and other adverse effects associated with these agents. Stavudine, in particular, is likely to cause peripheral neuropathy and lipoatrophy. Drugs with additive or overlapping toxicities, such as stavudine and didanosine, should not be combined. Zidovudine and stavudine, which compete intracellularly and therefore cause antagonism, should not be used together.
Drugs with similar mechanisms of action and resistance mutations (e.g., lamivudine and emtricitabine, or efavirenz and nevirapine) offer no significant advantage when combined and may increase toxicities. Certain three-drug combinations have suboptimal efficacy and are not recommended (e.g., tenofovir + didanosine + an NNRTI; tenofovir + emtricitabine + nevirapine; and three-NRTI regimens). Some ARVs require specific dosing intervals in particular patients. For example, once-daily dosing of lopinavir/ritonavir is not recommended for patients receiving concomitant efavirenz or nevirapine, and some once-daily PIs or combinations should not be used for treatment-experienced patients. For further information, see Tables 7 and 8 in the DHHS Guidelines.
Patients who start a new ARV regimen ideally should be seen at least twice within the first month to allow for an assessment of their adherence to therapy and the tolerability and adverse effects of the regimen.
When patients have been on a new regimen for 2-8 weeks, clinicians should check the following:
For further information, and for recommendations about monitoring stable patients, see chapter Initial and Interim Laboratory and Other Tests.
An ART regimen may fail for several reasons, including the following:
Note that the optimal management of immunologic failure is uncertain and is an active area of research. Consult with an HIV expert and consider referral to a research study.
If resistance is suspected, obtain an appropriate resistance test (see chapter Resistance Testing). Resistance testing is recommended, before changing regimens, in cases of virologic rebound during ARV therapy or suboptimal suppression of viral load on ARV therapy. Resistance testing often is crucial in identifying ARVs that are not likely to be effective against the patient's virus. It should be done while the patient is taking the failing regimen (or within 4 weeks of discontinuation) to maximize the likelihood that resistant viral populations will be present in detectable numbers. In virologic failure of a first regimen, it is fairly common to see resistance to only one or two drugs in a multidrug combination. The test results should be interpreted in the context of the patient's ARV history and the results of previous resistance tests.
Standard genotypes test give information about resistance that may affect NRTI, NNRTI, and PI agents. If integrase inhibitor (or fusion inhibitor) resistance is suspected, a specific genotype test must be ordered. There are no commercially available tests for resistance to CCR5 antagonists. For patients with virologic failure while taking a CCR5 antagonist, a coreceptor tropism assay should be considered (though the result does not rule out the possibility of resistance to CCR5 antagonists).
Cross-resistance exists among ARVs, such that resistance to one drug in a class of agents often extends to other drugs in that class. For example, cross-resistance between efavirenz and nevirapine is almost complete, and resistance mutations to NRTIs and to PIs often decrease viral susceptibility to other drugs in those classes. As a result, selecting a new ARV regimen can be complicated because it requires knowledge of expected resistance patterns. The likelihood of sustained viral suppression is lower when resistant virus is present even if a subsequent regimen contains new ARVs.
If treatment with a CCR5 antagonist is being considered, a tropism test must be obtained to verify that the patient has only CCR5-tropic virus (the currently available agent in this class is not effective in patients with any degree of CXCR4 virus). The standard test requires an HIV viral load of >1,000 copies/mL at the time of testing; a newer proviral DNA assay can identify coreceptor tropism in blood samples with HIV RNA levels below the limit of detection (this has not been clinically validated).
The following recommendations are adapted from the DHHS Guidelines.
Distinguish between the need to change a regimen because of drug intolerance or inability to adhere to the regimen and the failure to achieve the goal of sustained viral suppression. In the event of intolerability, single agents usually can be changed without resistance testing.
In general, do not change a single drug or add a single active drug to a failing regimen; it is important to use at least two or, preferably, three fully active ARVs (e.g., ARVs selected on the basis of resistance testing or because they are from a drug class to which the patient's virus has not been exposed). If resistance testing (performed while the patient is taking the failing regimen) shows resistance to only one agent in a regimen, it may be possible to replace only that drug; however, consultation with an expert is recommended.
In general, the goal of ART is to suppress HIV RNA to undetectable levels, in order to improve or maintain immune function. This usually is possible even for patients with resistance to multiple drugs as new ARV agents and new classes of ARVs have become available. Nevertheless, some patients have limited options for new regimens that will achieve durable virologic suppression. In some of these cases, it may be reasonable to continue the same regimen if partial virologic suppression and clinical and immunologic stability are maintained. The risk of continuing patients on a partially suppressive regimen, however, is the emergence of additional resistance mutations.
Data on the value of restarting a drug that the patient has previously received are limited. Resistant virus can be archived and will reemerge for patients who are rechallenged with regimens on which they had previously developed resistance. As a result, resistance tests from previous regimens should be used with current resistance tests to determine what drugs might be active in a new regimen.
Making the decision to change therapy and choosing a new ARV regimen require that the clinician have considerable expertise in the care of people with HIV infection. Those less experienced in the care of persons with HIV are strongly encouraged to obtain assistance by consulting with or referring to an expert.
These patients should continue their regular visits for monitoring, prophylaxis, and other medical treatment (see section Testing and Assessment for chapters on physical examinations and laboratory tests). ART should be discussed again and offered at regular intervals, if it is indicated, to anyone who initially refuses treatment. Routine clinic visits present ongoing chances to educate patients about new medications and research findings and to discuss the benefits of ART and the risks of delayed treatment. Decreases in patients' CD4 count or declines in their condition should be taken as opportunities to reassess their decisions about ARVs. If lack of readiness or probable adherence difficulties are at issue, an adherence counselor (if available) or a mental health provider should be engaged to bolster the patients' support and coping mechanisms (see chapter CD4 Monitoring and Viral Load Testing and the DHHS Guidelines).
It is not yet known whether ART has a long-term benefit when started during primary HIV infection, though there are a number of theoretic reasons why early treatment may reduce the severity of immune system disruption, lessen both the short-term and the long-term impact of HIV infection, and decrease the risk of HIV transmission. The DHHS Guidelines state that treatment of acute HIV is optional (except during pregnancy, when ART should be started as quickly as possible to reduce the risk of perinatal HIV transmission). However, for the appropriate patient, it is reasonable to consider starting therapy, with the goal of maximal virologic suppression. Before starting an ARV regimen, patients must be counseled carefully about potential limitations, such as toxicity, pill burden, cost, and the possible development of drug resistance. Patients should be monitored with HIV viral load, CD4 counts, and other parameters, as with patients with established infection who are receiving ART. Because no definitive data showing the clinical benefit of early treatment are available, persons with acute HIV infection ideally should be enrolled in clinical trials, if possible (see chapter Primary HIV Infection).
Combination ARV regimens are recommended for all women during pregnancy, regardless of CD4 count or HIV RNA level. The goal of ART for pregnant women is to reduce the risk of transmission to the infant and to treat HIV infection in the mother, through maximal virologic suppression. Obviously, the decision of whether to start ART during pregnancy is the choice of the woman, and her choice must be respected. There are a number of specific considerations about ART in pregnant women, including the timing of ART initiation (for those not already on treatment), specific ARVs that are recommended or that should be avoided (because of toxicity or teratogenicity concerns), pharmacokinetic variations and dosing requirements in pregnancy, and indications for resistance testing. See chapters Reducing Maternal-Infant HIV Transmission and Care of HIV-Infected Pregnant Women; also refer to the DHHS Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.
The presence of opportunistic infections is a strong signal of the need for ART and effective immune reconstitution. For some of these infections, ART is the primary therapy, and for others it is adjunctive. Although ART sometimes causes immune reconstitution inflammatory syndromes if initiated in the setting of acute opportunistic infection, limited clinical data for many such infections (including Pneumocystis jiroveci pneumonia and tuberculosis in persons with very low CD4 counts) suggest improved outcomes if ART is started early. Exceptions to this recommendation include cryptococcal meningitis, for which most experts recommend a short period of antifungal treatment before ART is started. For further information, see chapter Immune Reconstitution Inflammatory Syndrome and the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (see "References," below).
If treatment for either HIV or HBV is needed, treatment for both infections generally should be initiated, by including in the ART regimen two NRTIs with activity against both viruses (tenofovir + emtricitabine or tenofovir + lamivudine), if possible. The use of a single NRTI with activity against both viruses (resulting in monotherapy for HBV) is not recommended. If tenofovir is contraindicated, another anti-HBV drug should be used in combination with lamivudine or emtricitabine. Flares of HBV may occur if tenofovir, emtricitabine, or lamivudine is discontinued; monitor closely or consider substitution of another anti-HBV drug. See chapter Hepatitis B Infection and the DHHS Guidelines for additional information.
ART is a primary treatment for HIVAN and should be started urgently for patients with suspected HIVAN. See chapter Renal Disease.
The National HIV/AIDS Clinicians' Consultation Center is a valuable resource for any clinician seeking expert advice about ART, HIV clinical manifestations, laboratory evaluations, and other issues. Its National HIV Telephone Consultation Service (Warmline) is staffed by HIV-experienced physicians and pharmacists. The Warmline operates Monday through Friday, 8 a.m. to 8 p.m. eastern time and is available free of charge in the United States at 800-933-3413.