Antiretroviral Therapy

Background

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 (particularly >500 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. For patients with higher pretreatment CD4 levels, randomized and cohort studies also have found decreased rates of complications and death in those who initiated ART with CD4 counts of >350 cells/µL rather than <350 cells/µL, and some (though not all) observational evidence suggests a mortality benefit of ART among persons with CD4 counts of >500 cells/µL. 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 ongoing and 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:

  • Cardiovascular disease
  • Kidney disease, specifically HIV-associated nephropathy (HIVAN)
  • Liver disease, particularly among patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV)
  • Neurocognitive deficits, including dementia
  • Cancers, both AIDS-malignancies and non-AIDS malignancies

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 it sometimes fails (because of the patient's imperfect adherence or other factors). The failure of an ARV regimen when accompanied by drug resistance may mean that subsequent regimens are less likely to succeed, despite the availability of second-line ARV combinations.

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 (HHS) 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 balance between the potential benefit and the potential risk of ART has shifted strongly toward treatment for all willing individuals regardless of CD4 count, unless there are compelling reasons not to treat (see "When to Initiate Therapy: HHS ARV Guidelines," below; also see the HHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents for a full discussion of these issues).

Recent data also demonstrate that ART very substantially reduces the risk of transmission of HIV between serodiscordant heterosexual partners. The prevention effect of ART in men who have sex with men (MSM) and other risk groups has not yet been established in randomized controlled trials, but other lines of evidence suggest that ART strongly protects against HIV transmission in all risk groups. Thus, an additional benefit of earlier treatment with ART is a reduction in the risk of HIV transmission.

Of course, in deciding when to start ART for the individual patient, practitioners must weigh the expected benefits of ART for that person (e.g., improvements in health, reduction in HIV transmission) against the possible risks of ART (e.g., toxicity, drug resistance, adverse drug interactions). Patients must be willing to start and to continue on treatment, with an understanding that high levels of adherence are needed for treatment success.

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. HHS 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 HHS Guidelines are referenced frequently in this chapter.

HHS Guidelines: When to Start Therapy

The following recommendations have been adapted from the HHS Guidelines.

HHS guidelines recommend ART for all HIV-infected individuals, both for their own health and to prevent transmission:

"ART is recommended for all HIV-infected individuals to reduce the risk of disease progression. The strength and evidence for this recommendation vary by pretreatment CD4 cell count:"

ARV Treatment Recommendations to Prevent Disease Progression, by CD4 Count
CD4 countStrength
<350 cells/µLStrongly recommended
350-500 cells/µLStrongly recommended
>500 cells/µLModerately recommended

"ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV. The strength and evidence for this recommendation vary by transmission risks:"

ARV Treatment Recommendations for Prevention of Transmission of HIV
Transmission GroupStrength
Perinatal transmissionStrongly recommended
Heterosexual transmissionStrongly recommended
Other transmission risk groupsStrongly recommended

Note that these recommendations assume that resources are available for universal ART provision. In settings with limited resources, persons with lower CD4 counts or coexisting conditions (as below) may be prioritized.

ART also is strongly recommended for persons with certain conditions, regardless of CD4 count. These conditions include the following:

In some situations, ART may be needed relatively urgently. These include the following:

  • Pregnancy
  • Acute/recent HIV infection
  • AIDS-defining conditions
  • Acute opportunistic infections
  • HIVAN
  • HBV coinfection
  • HCV coinfection
  • Lower CD4 counts (e.g., <200 cells/µL)
  • Rapidly declining CD4 counts (e.g., >100 cells/µL/year)
  • Higher viral loads (e.g., >100,000 copies/mL)

S: Subjective

Obtain the patient's history and review of systems, including the following (see chapter Initial History):

  • CD4 cell count history, including nadir
  • HIV RNA (viral load) history, including pretreatment values if the patient is currently taking ARVs
  • History of HIV-related conditions
  • Previous and current ARV regimens, including start and stop dates, regimen efficacy, toxicity, resistance
  • Current medications, including herbal preparations, supplements, and over-the-counter medications
  • Medication allergies, intolerances, or prominent adverse effects
  • Comorbid conditions (e.g., HBV, HCV, depression)
  • Current and previous substance use, including alcohol and recreational drugs
  • Self-assessment of adherence to previous regimens
  • Desire to start or continue an ARV regimen
  • Commitment to adherence (see chapter Adherence)
  • Occupation and daily schedule
  • Willingness and indicators of ability to adhere to various types of regimens (e.g., QD, BID, with or without food) given current life situation
  • For women of childbearing potential: last menstrual period, current method of birth control (if any), current pregnancy status, thoughts on whether or when to have children

O: Objective

Perform the following objective tests:

  • Complete physical examination (see chapter Initial Physical Examination).
  • Current CD4 count and HIV viral load: preferably two or more separate results approximately 1 month apart.
  • Drug resistance test, as appropriate; to look for transmitted ARV resistance mutations, a genotype should be performed for all patients before initiating ART; this should be done as early in the course of infection as possible, because mutations may revert to wild-type. Review the results of previous resistance testing or obtain a baseline resistance test, if this was not done earlier; if a test was done in the past, consider retesting before ART is begun (see chapter Resistance Testing). Patients on ART whose viral loads are not suppressed also should undergo resistance testing.
  • Complete blood count (CBC) and platelet count, liver function tests (LFTs), renal function tests, fasting lipid panel, fasting glucose, rapid plasma reagin (RPR), tuberculin skin test, hepatitis serologies, Toxoplasma IgG, urinalysis, (see chapter Initial and Interim Laboratory and Other Tests).

A: Assessment

Make the following basic decisions:

  • This is or is not an appropriate time to start ART (e.g., do potential benefits of starting at this time outweigh the risks at this time?). See the HHS Guidelines noted above, which thoroughly address the issue, and note that many experts are increasingly concerned about the potential harm of untreated HIV infection, even in individuals with high CD4 cell counts. See chapters Risk of HIV Progression/Indications for ART and CD4 and Viral Load Monitoring.
  • The patient is or is not willing to start ARVs at this time (the choice to accept or decline therapy ultimately lies with the patient). If not, work with the patient on readiness issues, with more urgency if the CD4 count is low or the patient has symptoms, comorbidities, or coexisting conditions that suggest treatment is needed.
  • The patient is or is not likely to adhere to an ARV regimen (an adherence counselor, with or without a mental health clinician, may be able to assist with this assessment and should be called upon if available). No patient should be automatically excluded from consideration for ART; the likelihood of adherence must be discussed and determined individually (see chapter Adherence).

P: Plan

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 goals of therapy are to reduce HIV-related morbidity and mortality and to prevent HIV transmission; this includes improving the quality of life, maximally and durably suppressing HIV virus, and improving immune function and reducing HIV-associated inflammation.

Considerations Before Initiating ART

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 HHS 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:

  • Degree of immunodeficiency and risk of disease progression as reflected by the CD4 count and HIV RNA level. ART is more urgent for patients with lower or rapidly declining CD4 counts and also is less likely to be successful in those with low CD4 counts or very high HIV RNA levels (see "HHS Guidelines, When to Start Therapy." above, and chapters Risk of HIV Progression/Indications for ART and CD4 and Viral Load Monitoring)
  • Comorbidities
  • Potential benefits and risks of ARV drugs
  • Resistance, if any, to ARV medications (obtain resistance testing prior to ARV initiation for ARV-naive patients)

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.

Preparing the Patient for ART

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 primary goals of ART.

Supporting Adherence

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).

Anticipating Difficulties

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.

Considerations in Regimen Selection

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 adhere closely. The patient's comorbid conditions and potentially interacting medications should be evaluated for possible contraindications or synergism with ARVs. 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. Other factors should be evaluated with regard to specific ARV medications. For example, the HLA-B*5701 status and viral tropism should be determined if abacavir or maraviroc, respectively, are being considered: the HIV RNA level and creatinine clearance (CrCl) should be reviewed if rilpivirine or elvitegravir/cobicistat is being considered, and creatinine and Cr/Cl should be evaluated if tenofovir 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, FDA pregnancy categories and teratogenicity potential for specific ARVs should be taken into account. Drug interactions among ARVs or between ARVs and other medications should be evaluated, as dosage adjustments may be required or certain combinations may be contraindicated (see relevant tables in the HHS 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 HHS Guidelines.

Use of Multiple Classes of Drugs

For initial therapy in patients with wild-type HIV virus, the HHS Guidelines recommend the use of two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a nonnucleoside reverse transcriptase inhibitor (NNRTI), a ritonavir-boosted protease inhibitor (PI), or an integrase inhibitor (INSTI). Alternative types of combinations generally do not reduce virus levels as effectively as these recommended types. The question of whether to use an NNRTI, a PI, or an INSTI in initial therapy is a matter of debate. Some clinicians advocate using an NNRTI or INSTI 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 some INSTIs, and instead recommend starting with a PI-containing regimen. Each of the initial regimens proposed by the HHS Guidelines is highly effective if taken as directed, and each has specific advantages and disadvantages (see Table 6 of the HHS 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 HHS 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.

Boosted Protease Inhibitors

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 when used with certain other medications, in order to overcome drug-drug interactions (e.g., atazanavir must be boosted with ritonavir if tenofovir also is a component of the ARV regimen); see "Drug Interactions," below, and appropriate tables in the HHS Guidelines.

Preferred Starting Regimens

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 relevant tables in the HHS 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:

  • Abacavir + lamivudine (Epzicom)
  • Abacavir + lamivudine + zidovudine (Trizivir)
  • Tenofovir + emtricitabine (Truvada)
  • Zidovudine + lamivudine (Combivir)

One PI coformulation:

  • Lopinavir + ritonavir (Kaletra)

And three one-pill-per-day formulations of two NRTIs + one NNRTI or one INSTI:

  • Efavirenz + tenofovir + emtricitabine (Atripla)
  • Rilpivirine + tenofovir + emtricitabine (Complera)
  • Elvitegravir + cobicistat + tenofovir + emtricitabine (Stribild)

Other FDCs are in development and may become available in coming years.

The HHS 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 and should refer to the most up-to-date HHS guidelines. 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.

Table 1. Recommended Regimens for Initial Antiretroviral Treatment
ARV ClassPreferred RegimensAlternative Regimens

1. Efavirenz is teratogenic in nonhuman primates. Strongly consider alternative agent for women who plan to become pregnant or are not using effective and consistent contraception.

2. 3TC can be used in place of FTC and vice versa.

3. Should be considered only for patients with estimated CrCl ≥70 mL/min.

4. Abacavir should not be used by patients who test positive for HLA-B*5701; use with caution if HIV RNA level is >100,000 copies/mL or if there is a high risk of cardiovascular disease.

5. Rilpivirine is not recommended if the pretreatment HIV RNA is >100,000 copies/mL; caution if the CD4 count is <200 cells/µL.

Abbreviations: /r = low-dose ritonavir; INSTI = integrase inhibitor; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside/nucleotide analogue; PI = protease inhibitor

Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. Accessed December 1, 2013.

Note: Many other ART combinations are possible, and in some cases a different option may be most appropriate for the individual patient. The HHS Guidelines also list regimens that are "Acceptable," those that "May be acceptable," but are "less satisfactory" or lack definitive data, and several that "May be acceptable but should be used with caution"; see Table 5b in the HHS Guidelines.

NRTI based Efavirenz1 + ABC/3TC2,4

Rilpivirine5/TDF/FTC2

Rilpivirine5 + ABC/3TC2,4

NNRTI basedEfavirenz1/tenofovir/emtricitabine2 
PI basedAtazanavir/r + tenofovir/emtricitabine (TDF/FTC)2

Darunavir/r (QD) + TDF/FTC2

Atazanavir/r + ABC/3TC2,4

Darunavir/r + ABC/3TC2,4

Fosamprenavir/r (QD or BID) + ABC/3TC2,4 or TDF/FTC2

Lopinavir/r (QD or BID) + ABC/3TC2,4 or TDF/FTC2

INSTI based Raltegravir + TDF/FTC2

Elvitegravir/cobicistat/TDF/FTC2,3

Dolutegravir (QD) + abacavir/lamivudine (ABC/3TC)2,4

Dolutegravir (QD) + TDF/FTC2

Raltegravir + ABC/3TC4

Once-Daily Regimens

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 HHS Guidelines emphasize the importance of simple regimens and currently include six once-daily combinations among "preferred" regimens for initial therapy, and list a number of other possibilities among "alternative" regimens.

Avoiding Drug Resistance

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 INSTIs raltegravir and elvitegravir. It may take longer for high-level resistance to develop to other NRTIs and to ritonavir-boosted PIs, and perhaps also the INSTI dolutegravir. 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).

Drug Interactions

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 relevant tables in the HHS Guidelines.

Drugs and Drug Combinations That Should Not Be Used

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 drug combinations have suboptimal efficacy and are not recommended (e.g., tenofovir + didanosine as an NRTI backbone; 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 relevant tables in the HHS Guidelines.

Follow-Up of Patients Starting ART

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:

  • HIV viral load, to monitor initial virologic response to therapy, then every 4-8 weeks until the viral load is below the level of detection
  • CBC with platelets, for patients starting a zidovudine-containing regimen, to monitor for anemia
  • LFTs, to monitor for hepatotoxicity (patients starting a nevirapine-containing regimen should be monitored closely for the first 18 weeks of treatment)
  • Serum electrolytes, blood urea nitrogen, and creatinine (particularly for patients taking tenofovir)
  • Fasting glucose and lipids (after 1-3 months)

CD4 cell count should be checked after about 3 months.

For further information, and for recommendations about monitoring stable patients, see chapter Initial and Interim Laboratory and Other Tests.

Regimen Failure

An ART regimen may fail for several reasons, including the following:

Incomplete virologic response

  • Viral load is >200 copies/mL on consecutive tests after 24 weeks on therapy. (For some patients with multidrug resistance, it may not be possible to decrease plasma HIV viral load to undetectable levels, and stabilization of viral load below the previous baseline may be an appropriate goal of therapy.)

Virologic rebound

  • Virus is repeatedly detected in plasma (>200 copies/mL) after suppression to undetectable levels. Confirmatory testing is required to rule out "blips" of virus (isolated elevations in viral load of less than several hundred copies/mL) that are not clinically significant and to ensure that the increase is not caused by infection, vaccination, or problems with test methodology. Note that some patients may have persistently detectable low-level viremia (<200 copies/mL); the clinical significance of this is not clear.

Immunologic failure

  • Despite virologic suppression on ART, the CD4 cell count shows an inadequate response or a persistent decline.

Clinical progression

  • Recurrent, persistent, or new HIV-related illness occurs after ≥3 months on ART. Note that new or recurrent symptoms of opportunistic illness occurring in the first weeks to months after starting ART, especially in patients with severe immunosuppression, may not reflect a failure of ART. Rather, these symptoms could be attributable to persistence of opportunistic infections that may require longer treatment, or they could be caused by an immune reconstitution inflammatory syndrome (see chapter Immune Reconstitution Inflammatory Syndrome).

Responding to Apparent Treatment Failure

  • Carefully assess patient adherence, because inadequate adherence to ART is a common reason for regimen failure. In some cases, adherence support, treatment of adverse drug effects, substitution for poorly tolerated ARVs, or other measures to enhance adherence may result in virologic suppression (see chapter Adherence). In other cases, ARV resistance may have developed. Poor adherence may affect the decision to change therapy, and adherence issues should be addressed before a new regimen is initiated. If resistance is suspected, obtain an appropriate resistance test (or CCR5 tropism assay, if the patient is taking a CCR5 antagonist) while the patient is on the failing regimen; see below.
  • The availability of effective alternative ARVs is a critical consideration in deciding whether or when to change therapies. The development of new ARVs and new ARV classes in recent years has made virologic suppression possible for most patients, even those with extensive resistance. For the few patients in whom treatment possibilities are limited or nonexistent, it may be necessary to weigh the value of partial virologic suppression with the current regimen against the likelihood of further resistance developing. Strongly consider consultation with an experienced HIV provider and the use of HIV resistance testing when considering changes in therapy. When no treatment options remain among currently approved drugs, refer the patient to an appropriate clinical trial, if possible.

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.

Resistance and Coreceptor Tropism Testing

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 INSTI (or fusion inhibitor) resistance is suspected, a specific genotype test must be ordered. For patients with virologic failure while taking a CCR5 antagonist, a coreceptor tropism assay should be obtained (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, INSTIs, and 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, unless three ARVs that are fully active against the patient's virus can be included in the subsequent regimen.

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).

Suggestions for Changing an ARV Regimen for Suspected Drug Failure

The following recommendations are adapted from the HHS 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.

Follow-Up of Patients Not Started on ART

Patients who are not on ART

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 to anyone who initially refuses treatment. Routine clinic visits present ongoing chances to discuss the benefits of ART and the risks of delayed treatment, and to educate patients about new medications and research findings. 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 and Viral Load Monitoring and the HHS Guidelines).

Special Situations for ART

ART during acute or recent HIV infection

There are no definitive data that demonstrate long-term benefit if ART is started during early HIV infection, though emerging clinical data as well as theoretical considerations suggest early treatment may reduce the severity of immune system disruption and lessen both the short-term and the long-term impact of HIV infection. In addition early treatment may decrease the risk of HIV transmission during the highly infectious period of acute HIV. The HHS Guidelines recommend treatment of acute HIV (if identified during pregnancy, ART should be started as quickly as possible to reduce the risk of perinatal HIV transmission). 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. see chapter Early HIV Infection.

Pregnant women

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 for 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 Perinatal HIV Transmission and Care of HIV-Infected Pregnant Women; also refer to the HHS 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.

Older persons

Older persons with HIV infection may experience earlier development of a number of conditions that are associated with aging, such as cardiovascular disease and neurocognitive impairment. Additionally, older persons may have dampened immunologic responses to ART. For these reasons as well as others, ART initiation in older persons probably should not be delayed. Current HHS Guidelines recommend ART for all patients older than 50 years of age.

Acute opportunistic infections

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, clinical data for many such infections (including Pneumocystis jiroveci pneumonia and tuberculosis in persons with very low CD4 counts) suggest improved outcomes, including better survival, 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 the 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).

Hepatitis B coinfection

If treatment for either HIV or HBV is to be started, both infections generally should be treated simultaneously, 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 HHS Guidelines for additional information.

HIV-associated nephropathy

ART is a primary treatment for HIVAN and should be started urgently for patients with suspected HIVAN. See chapter Renal Disease.

Expert Consultation

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, 9 a.m. to 8 p.m. eastern time and is available free of charge in the United States at 800-933-3413.

Patient Education

  • Making the decision to start ART is rarely an emergency situation. Before starting patients on ART, health care providers must work with them to determine what goals of therapy are likely to be achieved, and which personal issues are pertinent for selecting the best regimen to fit their lifestyles,
  • Providers should review the proposed drug regimen with their patients. Be sure patients understand the instructions about dosage, scheduling, food requirements or restrictions, drug storage, adverse effects, toxicities, and type of reactions that must be reported immediately, as well as remedies for common adverse effects.
  • Providers should explain to patients that successful ART requires a commitment to taking the medications every day, as prescribed. If ARVs are taken incorrectly, HIV can quickly become resistant to the medications. This will mean even fewer choices and less-effective treatment in the future. It also may mean that patients could transmit resistant virus to a partner or, if they are pregnant, to an infant.
  • Patients should know that HIV medications may reduce the risk of HIV transmission substantially but do not offer perfect protection against infecting others. Recommend prevention measures such as using latex barriers during sex (safer sex) and not sharing needles or other drug-using equipment, even with other HIV-infected persons (see chapter Preventing HIV Transmission/Prevention with Positives for more information).
  • HCV, HBV, and other sexually transmitted diseases such as syphilis and gonorrhea can be transmitted between two HIV-infected partners.
  • Patients should be advised to check with their provider before discontinuing ARVs. If ARVs must be discontinued, it is usually best to stop all ARVs at once. The exception to this recommendation may be NNRTI-containing regimens. In this case, blood levels of the NNRTIs may be detectable for several weeks after discontinuation; if NRTIs are stopped, that may result in NNRTI monotherapy and the risk of NNRTI resistance. The optimal strategy for discontinuing NRTIs is not clear; some experts recommend continuing the NRTIs for a period of time after discontinuation of the NNRTI or switching from an NNRTI to a PI for some time before stopping all agents.
  • Patients should be encouraged to advise their provider of all other medications that they take, including over-the-counter medications, herbal remedies, and nutritional supplements.
  • Discuss contingencies in the event the client is unable to take ARVs for a day or more (e.g., illness, severe adverse effects, hospitalization, or other unexpected circumstances).

References