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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The primary goal of antiretroviral therapy (ART) is to reduce HIV-associated morbidity and mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication, as defined by achieving and maintaining plasma HIV RNA (viral load) below levels detectable by commercially available assays. Durable viral suppression improves immune function and quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. Based on emerging evidence, additional benefits of ART include a reduction in HIV-associated inflammation and possibly its associated complications.

Medical Therapy

Anti-HIV medications (also called antiretrovirals) are grouped into six drug classes according to their mechanism of action. The six classes are as follows:

  1. Non-nucleoside reverse transcriptase inhibitors (NNRTIs).
  2. Nucleoside reverse transcriptase inhibitors (NRTIs).
  3. Protease inhibitors (PIs).
  4. Fusion inhibitors.
  5. CCR5 antagonists.
  6. Integrase inhibitors.

Multidrug regimen has proved to be very beneficial because of reduction in progression to AIDS, opportunistic infections, rate of hospitalizations and deaths. [1]

Chapter Outline

This chapter in outlined as follows:

Guidelines for Initiation of ART | Indications | Selection of the Regimen | Treatment-naive Patients | Treatment-experienced Patients | Initial HIV Therapy | Highly Active Anti-Retroviral Therapy | Special Considerations | HIV in Children
Difficulty in Adherence | Importance of Adherence
Visit Frequency | General Laboratory Investigations | Virologic Response | Virologic Failure | Viral Blips

Goals of Therapy

DHHS ART Guidelines present the following goals for therapy:

  • Durable suppression of HIV viral load ( to <50 cells/mL ).
  • Restoration of normal CD4 cell count.
  • Prevention of transmission of the disease.
  • Prevention of building of drug resistance.
  • Improvement in quality of life of the patient.

Uncontrolled viremia causes inflammation and immune activation, which has an overall effect on cardiovascular, renal and hepatic systems. Controlling viremia also controls these effects.

Anti Retroviral Therapy (ART)

Guidelines for Initiation of ART

Year AIDS/Symptoms CD4 <200 CD4 200-350 CD4 350-500 CD4 >500
DHHS [2] 2011 Yes Yes Yes Yes Yes (optional)
IAS-USA[2] 2010 Yes Yes Yes Yes Consider
UK 2008 Yes Yes Yes Clinical trial Clinical trial
EACS[3] 2011 Yes Yes Yes Consider Defer
WHO [[3]] 2010 Yes Yes Yes No No

Indications

The DHHS guidelines currently recommend the follwing:

Symptoms CD4 count Treatment
Asymptomatic <500 Treatment should be offered.
Asymptomatic >500 Treatment is optional.
Symptomatic Any value Treatment should be initiated.[2]

Selection of the Regimen

A. US Department of Health and Human Services (DHHS)

DHHS have published guidelines for initial ART based on data from randomized controlled trials. Current optimal HAART options consist of combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of antiretroviral agents.

Typical regimens consist of:

Following regimens are recommended by DHHS:

  • An integrase inhibitor, raltegravir (400 mg twice daily) with 2 NRTIs.

The recommended NRTI coformulation is tenofovir/emtricitabine (TDF/FTC) in all of the above combinations. In treatment-naive patients, four drug regimen is not found to be more efficacious than three-drug regimens and is associated with more adverse events.[4][5]

B. International AIDS Society-USA (IAS-USA) Guidelines

In agreement with the DHHS guidelines mentioned above, IAS-USA recommend the following:[2]

  • Fixed-dose TDF/FTC as the preferred NRTI for combination ART.
  • If HLA B5701 testing is negative, then abacavir/lamivudine is used as an alternative choice.

Treatment-naive Patients

The DHHS Guidelines recommend that therapy should be initiated in the following patient populations:

  • Patients with history of an AIDS-defining illness or with a CD4 count of less than 350/µL.
  • Patients with HIV and hepatitis B virus (HBV) coinfection who require treatment for HBV infection.

Fusion inhibitors (eg, enfuvirtide) are not approved for treatment-naive patients.

Treatment-experienced Patients

Treatment failure is defined by the following factors:

  • Virologic failure: which is defined as suboptimal viral suppression or loss of suppression (>50 HIV-1 RNA copies/mL).
  • Immunologic failure : which is defined as failure to achieve or maintain CD4 cell count recovery despite effective viral suppression.

Initial HIV Therapy

NNRTI, PI, or integrase inhibitor-based regimen in combination with dual NRTIs is considered as an initial HIV therapy. Currently, CCR5 inhibitors are not recommended due to lack of sufficient published data. The particular choice of agent depends on the following factors:

  • Side effect profiles.
  • Comorbidities in patient.
  • Potential drug interactions.
  • Allergy history.
  • Pregnancy status.
  • Patient convenience.

Highly Active Anti-Retroviral Therapy

  • Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART.[6] This has been highly beneficial to many HIV-infected individuals since its introduction in 1996 when the protease inhibitor-based HAART initially became available.
    Abacavir – a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)
  • In developed countries where HAART is available, doctors assess the viral load, rapidity in CD4 decline, and patient readiness while deciding when to recommend initiating treatment.[7]
  • In the absence of HAART, progression from HIV infection to AIDS occurs at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months.
  • HAART is thought to increase survival time by between 4 and 12 years.[8][9] This average reflects the fact that for some patients – and in many clinical cohorts this may be more than fifty percent of patients – HAART achieves far less than optimal results. This is due to a variety of reasons such as medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV.
  • Non-adherence and non-persistence with antiretroviral therapy is the major reason most individuals fail to get any benefit from and develop resistance to HAART.[10]
  • The side effects include lipodystrophy, dyslipidaemia, insulin resistance, an increase in cardiovascular risks and birth defects.[11][12]
  • Side-Effect of HAART: Treatment optimism after the initial successes of HAART likely affected the subsequent dynamics of HIV because these favorable treatment outcomes led some persons to increase their high-risk behavior.

Special Considerations

  • HAART allows the stabilization of the patient’s symptoms and viremia, but it neither cures the patient of HIV, nor alleviates the symptoms, and high levels of HIV-1, often HAART resistant, return once treatment is stopped.[13][14] Moreover, it would take more than the lifetime of an individual to be cleared of HIV infection using HAART.[15] Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to the plummeting of HIV-associated morbidity and mortality.[16][17][18]

HIV in Children

Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, particularly for young infants, treatment recommendations are more aggressive for children than for adults.[19]

Treatment Adherence

Adherence is taking the correct dose of each anti-HIV medication at the correct time and exactly as prescribed. Adherence is very important for successful HIV treatment. The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues, along with side effects that create intentional non-adherence, also has a weighty impact.[20][21][22]

Difficulty in Adherence

There are several reasons why adhering to an HIV treatment regimen can be diicult. Most treatment regimens involve taking several pills every day with or without food, or before or after other medications. Other factors that can make treatment adherence difficult include:

  • Difficulty taking medications (such as trouble swallowing pills).
  • Side effects from medications (for example, fatigue or diarrhea).
  • Daily schedule issues (including a busy schedule, shift work, or travel away from home) .
  • Being sick or depressed .
  • Alcohol or drug abuse.

Importance of Adherence

Adherence effects the success of HIV treatment in two ways:

  • Good adherence to an HIV treatment regimen helps anti-HIV medications work effectively to reduce the viral load. Skipping medications, even occasionally, gives HIV to multiply rapidly. Preventing the virus from multiplying is the best way to stay healthy.
  • Good adherence to an HIV treatment regimen also helps prevent drug resistance. One or more anti-HIV medications in a treatment regimen can become ineffective as a result of drug resistance.

Skipping medications makes it easier for drug resistance to develop. HIV can develop resistance to the anti-HIV medications in a person’s current regimen or to other, similar anti-HIV medications not yet taken, limiting options for successful HIV treatment. And drug-resistant strains of HIV can be transmitted to others, too. Although there are many different anti-HIV medications and treatment regimens, studies show that a person’s first regimen offers the best chance for long-term treatment success. Adhering to the regimen from the start will help ensure that the HIV treatment is successful.

Patient Monitoring during ART

A patient monitoring system is the backbone of clinical care, treatment and prevention by the clinical team caring for groups of patients.

Visit Frequency

Patients who are started on ART should generally have follow-up within one to two weeks. Patient should be asked about the following:

Visit frequency of patients who are clinically stable on their ART regimen, can be decrease to every three months.

General Laboratory Investigations

The following lab tests are advised at baseline and at scheduled follow-up:

More frequent testing is indicated in the following conditions:

Virologic Response

The most reliable indicator of response to ART is plasma HIV RNA and should be measured in all patients at baseline and regularly during therapy.[24][25] It is thus useful in predicting clinical progression.

Viral load reduction may be more rapid in following patients:[26]

  • Having high CD4 cell count.
  • Having lower levels of baseline viremia.
  • In treatment-naive patients.
Time Expected decrease in Viral load
1 week decrease by 0.75 to 1 log10 copies/mL
1 month decrease by 1.5 to 2 log10 copies/mL to <5000 copies/mL .
2 to 4 months. <500 copies/mL
4 to 6 months. < 50 copies/mL.


Transient increase in the viral load can be present in acute illness and vaccinations.

Virologic Failure

It is defined either as primary failure to achieve a viral load <50 copies/mL or any sustained recurrence of viremia to >50 copies/mL after initial viral suppression.[2]

Two main causes of the failure are:

  1. Drug resistance.
  2. Failure of the drugs to reach the target site.

Viral Blips

It refer to an isolated low-level of detectable HIV RNA (>50 to 500 copies/mL) that occurs during long-term monitoring on a stable ART regimen.[27]

Department of Health and Human Services (DHHS) have suggested that viral blips do not require intervention with a new regimen unless the viral load is sustained at >200 copies/mL.

Indications for Modification of Therapy

Common indications for the change of therapy are as follows:

  • Virologic failure : It should be confirmed with a second test before any treatment modification is considered.
  • Toxicity
  • Intolerance
  • Inconvenience

Alternate Therapies

Various forms of alternative medicine have been used to treat symptoms or alter the course of the disease.[28] In the first decade of the epidemic when no useful conventional treatment was available, a large number of people with AIDS experimented with alternative therapies. The definition of "alternative therapies" in AIDS has changed since that time. Then, the phrase often referred to community-driven treatments, untested by government or pharmaceutical company research, that some hoped would directly suppress the virus or stimulate immunity against it. Examples of alternative medicine that people hoped would improve their symptoms or their quality of life include massage, stress management, herbal and flower remedies such as boxwood,[29][30] and acupuncture;[28] when used with conventional treatment, many now refer to these as "complementary" approaches. Despite the widespread use of complementary and alternative medicine by people living with HIV/AIDS, the effectiveness of these therapies has not been established.[31]

NIH Recommendations

NIH Recommendations:Treatment-Naive Patients

NIH Recommendations for Initiating Antiretroviral Therapy in Treatment-Naive Patients

  • Antiretroviral therapy (ART) is recommended for all HIV-infected individuals. The strength of this recommendation varies on the basis of pretreatment CD4 cell count:
    • CD4 count <350 cells/mm3 (AI)
    • CD4 count 350 to 500 cells/mm3 (AII)
    • CD4 count >500 cells/mm3 (BIII)
  • Regardless of CD4 count, initiation of ART is strongly recommended for individuals with the following conditions:
  • Effective ART also has been shown to prevent transmission of HIV from an infected individual to a sexual partner; therefore, ART should be offered to patients who are at risk of transmitting HIV to sexual partners (AI [heterosexuals] or AIII [other transmission risk groups].
  • Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case by case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.

What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient

The Panel recommends the following as preferred regimens for antiretroviral (ARV)-naive patients:

  • efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) (AI)
  • ritonavir-boosted atazanavir + tenofovir/emtricitabine (ATV/r + TDF/FTC) (AI)
  • ritonavir-boosted darunavir + tenofovir/emtricitabine (DRV/r + TDF/FTC) (AI)
  • raltegravir + tenofovir/emtricitabine (RAL + TDF/FTC) (AI).
  • Selection of a regimen should be individualized on the basis of virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, and comorbid conditions.
  • Based on individual patient characteristics and needs, in some instances, an alternative regimen may actually be a preferred regimen for a patient.

NIH Recommendations:Treatment-Experienced Patient

NIH recommendations for Virologic and Immunologic Failure

Assessing and managing an antiretroviral (ARV)-experienced patient experiencing failure of antiretroviral therapy (ART) is complex. Expert advice is critical and should be sought.

  • Evaluation of virologic failure should include an assessment of the severity of the patient’s HIV disease, ART history, use of concomitant medications with consideration of adverse drug interactions with ARV agents, HIV RNA and CD4 T-cell count trends over time, and prior drug-resistance testing results.
  • Drug-resistance testing should be obtained while the patient is taking the failing ARV regimen or within 4 weeks of treatment discontinuation (AII).
  • The goal of treatment for ARV-experienced patients with drug resistance who are experiencing virologic failure is to reestablish virologic suppression (e.g., HIV RNA <48 copies/mL) (AI).
  • To design a new regimen, the patient’s treatment history and past and current resistance test results should be used to identify at least two (preferably three) fully active agents to combine with an optimized background ARV regimen (AI). A fully active agent is one that is likely to have ARV activity on the basis of the patient’s treatment history, drug-resistance testing, and/or a novel mechanism of action.
  • In general, adding a single, fully active ARV in a new regimen is not recommended because of the risk of rapid development of resistance (BII).
  • In patients with a high likelihood of clinical progression (e.g., CD4 count <100 cells/mm3) and limited drug options, adding a single drug may reduce the risk of immediate clinical progression, because even transient decreases in HIV RNA and/or transient increases in CD4 cell counts have been associated with clinical benefits (CI).
  • For some highly ART-experienced patients, maximal virologic suppression is not possible. In this case, ART should be continued (AI) with regimens designed to minimize toxicity, preserve CD4 cell counts, and avoid clinical progression.
  • Discontinuing or briefly interrupting therapy in a patient with viremia may lead to a rapid increase in HIV RNA and a decrease in CD4+ cell count and increases the risk of clinical progression. Therefore, this strategy is not recommended (AI).
  • In the setting of virologic suppression, there is no consensus on how to define or treat immunologic failure.

NIH recommendations for Exposure-Response Relationship and Therapeutic Drug Monitoring

  • Therapeutic drug monitoring (TDM) for antiretroviral (ARV) agents is not recommended for routine use in the management of the HIV-infected adult (CIII).
  • TDM may be considered in selected clinical scenarios, as discussed in the text below.

NIH recommendations for Considerations for Antiretroviral Use in Special Patient Populations

Special Patient Populations: Acute HIV Infection
  • It is unknown if treatment of acute HIV infection results in long-term virologic, immunologic, or clinical benefit; treatment should be considered optional at this time (CIII).
  • Therapy should also be considered optional for patients with HIV seroconversion in the previous 6 months (CIII).
  • All pregnant women with acute or recent HIV infection should start a combination antiretroviral (ARV) regimen as soon as possible to prevent mother-to-child transmission (MTCT) of HIV (AI).
  • If the clinician and patient elect to treat acute HIV infection, treatment should be implemented with the goal of suppressing plasma HIV RNA to below detectable levels (AIII).
  • For patients with acute HIV infection in whom therapy is initiated, testing for plasma HIV RNA levels and CD4 count and toxicity monitoring should be performed as described for patients with established, chronic HIV infection (AII).
  • If the decision is made to initiate therapy in a person with acute HIV infection, genotypic resistance testing at baseline will be helpful in guiding the selection of an ARV regimen that can provide the optimal virologic response; this strategy is therefore recommended (AIII). If therapy is deferred, genotypic resistance testing should still be performed because the result may be useful in optimizing the virologic response when therapy is ultimately initiated (AIII).
  • Because clinically significant resistance to protease inhibitors (PIs) is less common than resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) in antiretroviral therapy (ART)-naive persons who harbor drug-resistant virus, a ritonavir (RTV)-boosted PI-based regimen should be used if therapy is initiated before drug resistance test results are available (AIII).
Special Patient Populations: HIV-Infected Women
  • The indications for initiation of antiretroviral therapy (ART) and the goals of treatment are the same for HIV-infected women as for other HIV-infected adults and adolescents (AI).
  • Women taking antiretroviral (ARV) drugs that have significant pharmacokinetic interactions with oral contraceptives should use an additional or alternative contraceptive method to prevent unintended pregnancy (AIII).
  • In pregnant women, an additional goal of therapy is prevention of perinatal transmission of HIV, with a goal of maximal viral suppression to reduce the risk of transmission of HIV to the fetus and newborn (AI).
  • When selecting an ARV combination regimen for a pregnant woman, clinicians should consider the known safety, efficacy, and pharmacokinetic data on use during pregnancy for each agent (AIII).
  • Use of efavirenz (EFV) should be avoided in a pregnant woman during the first trimester or in a woman who desires to become pregnant or who does not or cannot use effective and consistent contraception (AIII).
  • Clinicians should consult the most current Health and Human Services (HHS) Perinatal Guidelines when designing a regimen for a pregnant woman (AIII).
Special Patient Populations: Older Patient

Key Considerations When Caring for Older HIV-Infected Patients

  • Antiretroviral therapy (ART) is recommended in patients >50 years of age, regardless of CD4 cell count (BIII), because the risk of non-AIDS related complications may increase and the immunologic response to ART may be reduced in older HIV-infected patients.
  • ART-associated adverse events may occur more frequently in older HIV-infected adults than in younger HIV-infected individuals. Therefore, the bone, kidney, metabolic, cardiovascular, and liver health of older HIV-infected adults should be monitored closely.
  • The increased risk of drug-drug interactions between antiretroviral (ARV) drugs and other medications commonly used in older HIV-infected patients should be assessed regularly, especially when starting or switching ART and concomitant medications.
  • HIV experts and primary care providers should work together to optimize the medical care of older HIV-infected patients with complex comorbidities.
  • Counseling to prevent secondary transmission of HIV remains an important aspect of the care of the older HIV infected patient.

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References

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  25. ↑ Hughes MD, Johnson VA, Hirsch MS, Bremer JW, Elbeik T, Erice A, Kuritzkes DR, Scott WA, Spector SA, Basgoz N, Fischl MA, D'Aquila RT (1997). "Monitoring plasma HIV-1 RNA levels in addition to CD4+ lymphocyte count improves assessment of antiretroviral therapeutic response. ACTG 241 Protocol Virology Substudy Team". Ann. Intern. Med. 126 (12): 929–38. PMID 9182469. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  26. ↑ Gottlieb GS, Sow PS, Hawes SE, Ndoye I, Redman M, Coll-Seck AM, Faye-Niang MA, Diop A, Kuypers JM, Critchlow CW, Respess R, Mullins JI, Kiviat NB (2002). "Equal plasma viral loads predict a similar rate of CD4+ T cell decline in human immunodeficiency virus (HIV) type 1- and HIV-2-infected individuals from Senegal, West Africa". J. Infect. Dis. 185 (7): 905–14. doi:10.1086/339295. PMID 11920314. Retrieved 2012-02-19. Unknown parameter |month= ignored (help)
  27. ↑ Sungkanuparph S, Overton ET, Seyfried W, Groger RK, Fraser VJ, Powderly WG (2005). "Intermittent episodes of detectable HIV viremia in patients receiving nonnucleoside reverse-transcriptase inhibitor-based or protease inhibitor-based highly active antiretroviral therapy regimens are equivalent in incidence and prognosis". Clin. Infect. Dis. 41 (9): 1326–32. doi:10.1086/496985. PMID 16206110. Retrieved 2012-02-21. Unknown parameter |month= ignored (help)
  28. ↑ 28.0 28.1 Saltmarsh S (2005). "Voodoo or valid? Alternative therapies benefit those living with HIV". Positively Aware. 3 (16): 46. PMID 16479668.
  29. ↑ Pharo A; et al. (1996). "Evaluation of the safety and efficacy of SPV-30 (boxwood extract) in patients with HIV disease". Int Conf AIDS (Jul 7–12): 11:19. abstract no. Mo. B.180.
  30. ↑ Durant J; et al. (1998). "Efficacy and safety of Buxussempervirens L. preparations (SPV-30) in HIV infected asymptomatic patients: a multi-centre, randomized, double-blind, placebo-controlled trial". Phytomedicine (5): 1–10.
  31. ↑ Mills E, Wu P, Ernst E (2005). "Complementary therapies for the treatment of HIV: in search of the evidence". Int. J. STD AIDS. 16 (6): 395&ndash, 403. PMID 15969772.
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