1 Star2 Stars3 Stars4 Stars5 Stars (No Ratings Yet)
blankLoading...

Antiretroviral Therapy in Previously Treated Adults

Antiretroviral regimens should be modified in individuals receiving a regimen considered to be suboptimal (e.g., monotherapy or a 2-drug regimen that includes only NRTIs); individuals who are experiencing toxicity or intolerance on their current regimen; individuals who have who had an initial response to a potent regimen and undetectable plasma HIV-1 RNA levels but are now experiencing disease progression or have detectable levels of plasma HIV-1 RNA; and individuals who have been receiving a potent regimen and whose viral load was never suppressed below the limits of detection.

Optimal antiretroviral therapy involves continuous evaluation of the patient’s response to the current regimen since the duration of clinical benefit from any one antiretroviral regimen may be limited.

A decision to change a patient’s antiretroviral regimen should be made after careful consideration of several factors, including recent clinical history and physical examination, plasma HIV-1 RNA levels (measured on 2 separate occasions), absolute CD4+ T-cell counts and changes in these counts, potency of remaining treatment options, potential resistance patterns associated with prior antiretroviral regimens, and issues related to compliance, tolerance, and possible drug interactions with the new regimen.

Whenever a change in antiretroviral therapy is considered in a previously treated individual, it is important to distinguish between the need to change therapy because of drug toxicity or drug failure and to carefully assess patient adherence to the prior regimen.

A review of the agents that the patient already has received is essential. Resistance testing (performed while the patient is still receiving the old regimen) is useful in maximizing the number of active drugs in the new regimen.

Viral resistance is an important, but not the only, reason for treatment failure. Viral mutants will emerge in all HIV-infected patients over time; however, use of potent regimens that provide durable suppression of HIV replication are less likely to result in rapid emergence of resistant strains. The new regimen should include antiretrovirals that are predicted to provide maximal suppression of HIV replication while avoiding use of those that might be ineffective.

Definitions and Causes of Treatment Regimen Failure

Failure of a treatment regimen may be the result of poor patient compliance, poor tolerability, pharmacokinetic issues (including drug-food or drug-drug interactions), suboptimal virologic potency, and resistance factors. Failure of a regimen can be associated with virologic failure, immunologic failure, and/or clinical failure. Some patients may have discordant virologic, immunologic, or clinical responses and each of these have distinct time courses and may occur independently or simultaneously. 3 In general, virologic failure occurs first, followed by immunologic failure and then clinical failure.

Virologic Failure

Virologic failure of a treatment regimen refers specifically to an incomplete (or lack of) plasma HIV-1 RNA response. An incomplete virologic response is defined as failure to suppress plasma HIV-1 RNA levels to less than 400 copies/mL after 24 weeks or to less than 50 copies/mL after 48 weeks of antiretroviral therapy in treatment-naive patients. Baseline HIV-1 RNA levels may impact the time course of response and some patients may take longer to suppresses viremia than others. The timing, pattern, and/or slope of the HIV-1 RNA decrease may predict ultimate virologic response; most patients with an adequate virologic response at week 24 had at least a 1 log reduction 1-4 weeks after starting therapy.

Virologic rebound is another form of virologic failure and is defined as repeated detection of virus in plasma after initial suppression.

The optimal time to change therapy for low-level viremia remains to be determined. One approach (the most aggressive) is to change the antiretroviral regimen for repeated detectable viremia (e.g., 2 consecutive plasma HIV-1 RNA levels exceeding 400 copies/mL after suppression to less than 400 copies/mL on the current regimen). Another approach is to allow detectable viremia up to a certain level (e.g., 1000-5000 copies/mL); however, ongoing viral replication in the presence of antiretroviral agents promotes selection of drug resistant mutations. While isolated episodes of viremia (e.g., single levels of 500-1000 copies/mL) usually are not associated with subsequent virologic failure, episodes of higher viral loads or frequent episodes of viremia increase the risk of failure.

Immunologic Failure

Immunologic failure is defined as failure to increase CD4+ T-cell counts 25-50/mm3 over baseline during the first year of therapy or a decrease in CD4+ T-cell counts from baseline while receiving therapy. An increase in CD4+ T-cell counts of 150/mm3 over the first year of therapy occurs in most treatment-naive patients receiving an initial regimen.

Clinical Failure

Clinical failure is defined as the occurrence or recurrence of HIV-related events after at least 3 months of antiretroviral therapy, excluding immune reconstitution syndrome.

Considerations When Changing an Antiretroviral Regimen

If a change in the antiretroviral regimen is being made because of problems with adherence, other conditions that may reduce adherence (e.g., depression, substance abuse) should be addressed and the regimen should be simplified (e.g., changes made to lower pill burden or increase dosing interval).

If a change in the regimen is being made because of drug toxicity or intolerance, one agent from the same antiretroviral class as the drug causing the toxicity can be substituted (e.g., stavudine for zidovudine-related anemia or GI symptoms; nevirapine for efavirenz-related CNS symptoms) or an agent from another antiretroviral class can be substituted for the drug causing the toxicity (e.g., changing from an HIV protease inhibitor to an NNRTI).

If a change is being made because of pharmacokinetic issues, food/fasting requirements should be reviewed, the possibility of malabsorption assessed, and concomitant drugs and dietary supplements reviewed for possible drug-drug interactions and changes in the antiretroviral regimen and/or concomitant therapy should be made if possible.

If a change is being made because of virologic failure, a distinction needs to be made between patients with limited antiretroviral exposure and patients with extensive prior treatment. The goal of therapy in patients with limited antiretroviral experience is maximum viral suppression and prevention of further selection of resistant mutations. The goal of therapy in patients with extensive antiretroviral experience is preservation of immune function and prevention of clinical progression; viral suppression is difficult to achieve in these patients and is not a goal of therapy.

A change in the regimen may not be warranted in patients with immunologic or clinical failure if viremia is being adequately suppressed.

Ideally, the new regimen should consist of 3 or more active drugs. Active drugs are evaluated on the basis of resistance testing or different mechanism of action; a drug that the patient has not taken is not necessarily active because cross-resistance can occur within antiretroviral drug classes. Drug potency also is a consideration; drug potency is more important than the number of drugs.

Factors associated with improved virologic response to subsequent regimens include low HIV RNA levels at the time of therapy change, change to a new antiretroviral class, and use of a regimen that includes a ritonavir-boosted HIV protease inhibitor regimen (low-dose ritonavir with another HIV protease inhibitor) in HIV protease inhibitor-experienced patients.

Some degree of cross-resistance can occur among the various HIV protease inhibitors. Initial use of amprenavir, atazanavir, nelfinavir, or saquinavir is associated with early novel mutations that do not confer cross-resistance to other HIV protease inhibitors. Continued use of these HIV protease inhibitors results in the accumulation of additional mutations that confer cross-resistance to the entire class of antiretrovirals.

Following long-term use, cross-resistance commonly occurs among NRTIs. Most NNRTI-associated resistance mutations confer resistance to the entire class.

Recommendations for Changing an Antiretroviral Regimen in Specific Clinical Situations

If the current antiretroviral regimen appears ineffective because plasma HIV-1 RNA levels are low but not adequately suppressed (i.e., plasma HIV-1 RNA levels up to 5000 copies/mL) in patients with limited prior antiretroviral experience, options include intensifying the regimen by addition of one drug (e.g., tenofovir), pharmacokinetic enhancement (e.g., addition of low-dose ritonavir to an HIV protease inhibitor-based regimen), or changing to a completely new regimen.

If the current antiretroviral regimen appears ineffective in patients with limited prior antiretroviral experience because of resistance to one drug, options include changing that one drug, pharmacokinetic enhancement (e.g., addition of low-dose ritonavir to a HIV protease inhibitor-based regimen), or changing to a completely new regimen.

If the current antiretroviral regimen appears ineffective in patients with limited prior antiretroviral experience because of resistance to more than one drug, options include changing antiretroviral classes (e.g., HIV protease inhibitor-based regimen to an NNRTI-based regimen or vice versa) and/or adding new active drugs.

If the current antiretroviral regimen appears ineffective but no resistance is identified, options include continuing the same regimen or starting a new regimen and repeating genotypic testing early (e.g., 2-4 weeks).

If the current antiretroviral regimen appears ineffective in patients who have received extensive antiretroviral therapy, options include continuing the same antiretroviral regimen if there are few or no other treatment options available. Drugs with a new mechanism of action (i.e., enfuvirtide) have antiretroviral activity in treatment-experienced patients with multidrug resistance. Adding a single active drug to a failing regimen is not recommended because of the risk of rapidly development of resistance to the new drug.

However, in patients with advanced HIV with a high likelihood of clinical progression (e.g., CD4+ T-cell count less than 100/mm3), adding a single drug may reduce the risk of immediate clinical progression since even a transient decrease in HIV-1 RNA levels and/or transient increases in CD4+ T-cell counts have been associated with clinical benefit. Weighing the risks (selection of drugs resistance) and benefits (short-term antiretroviral activity) of adding a single active drug in a heavily treatment-experienced patient is complicated, and consultation with an expert is advised.

The recommended treatment option for patients who experience virologic failure while receiving an initial antiretroviral regimen that is an NNRTI-based regimen (1 NNRTI and 2 NRTIs) is a regimen that includes an HIV protease inhibitor (with or without low-dose ritonavir) and 2 NRTIs (selected based on resistance testing).

For patients who experienced virologic failure while receiving an initial regimen that is an HIV protease inhibitor-based regimen (1 HIV protease inhibitor with or without low-dose ritonavir and 2 NRTIs), a new regimen that includes an NNRTI and 2 NRTIs (selected based on resistance testing) is recommended.

There are several recommended regimens for patients who experience virologic failure while receiving an initial triple NRTI regimen; these patients can be changed to an NNRTI-based regimen (1 NNRTI and 2 NRTIs selected based on resistance testing), an HIV protease inhibitor-based regimen (1 HIV protease inhibitor with or without low-dose ritonavir and 2 NRTIs selected based on resistance testing), a regimen that includes an NNRTI and an HIV protease inhibitor (with or without low-dose ritonavir), or a regimen that includes an NNRTI, an HIV protease inhibitor (with or without low-dose ritonavir), and NRTIs (selected based on resistance testing).

Antiretroviral Therapy in Pediatric Patients

The same general principles of antiretroviral therapy that apply to HIV-infected adults also apply to HIV-infected pediatric patients; however, the treatment of HIV-infected neonates, children, and adolescents involves unique pharmacologic, virologic, and immunologic considerations. In 1993, the Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children, a panel convened by the National Pediatric and Family HIV Resource Center (NPHRC), the Health Resources and Services Administration (HRSA), and the National Institutes of Health (NIH) first issued guidelines for the use of antiretroviral agents in the treatment of HIV-infected children. At that time, monotherapy with zidovudine or didanosine was considered an appropriate regimen for initial therapy in HIV-infected pediatric patients.

However, based on studies evaluating multiple-drug antiretroviral regimens in pediatric patients and information regarding the benefits of antiretroviral regimens in HIV-infected adults, the guidelines have been revised several times and now include recommendations for use of multiple-drug antiretroviral regimens for the treatment of pediatric HIV infection. The most recent guidelines for use of antiretrovirals in pediatric HIV infection include information on the diagnosis of HIV in infants; criteria for when to initiate and how to monitor antiretroviral therapy in neonates, children, and adolescents; recommendations for antiretroviral regimens that can be used for initial therapy in pediatric patients; clinical, immunologic, and virologic criteria that can be used to determine when to alter the initial antiretroviral regimen; and information regarding the management of adverse drug reactions in pediatric patients.

Because recommendations for the management of HIV infection in neonates, children, and adolescents are rapidly evolving and increasingly complex, it is recommended that management of HIV-infected pediatric patients be directed by a clinician with expertise in the treatment of pediatric and adolescent HIV infection whenever possible, or that such a specialist be consulted regularly throughout the course of treatment to obtain the most up-to-date information.

Antiretroviral therapy is recommended for all HIV-infected children who have clinical symptoms of HIV infection or evidence of immunosuppression, regardless of age or plasma HIV-1 RNA levels. Ideally, antiretroviral therapy should be initiated in all HIV-infected infants younger than 12 months of age as soon as a confirmed diagnosis is established, regardless of clinical or immunologic status or viral load. There has been some controversy regarding use of antiretrovirals in children 12 months of age or older with asymptomatic HIV infection.

Safety and efficacy of some of the antiretroviral agents in pediatric patients have not been definitely established. However, the absence of results of controlled clinical trials evaluating the drug in pediatric patients should not preclude the use of a commercially available antiretroviral agent when it is indicated in an HIV-infected child, provided current knowledge regarding the drug’s pharmacokinetics and safety are taken into consideration.

Considerable information is available regarding use of NRTIs in pediatric patients. Zidovudine and didanosine have been used extensively in HIV-infected children either alone or in antiretroviral regimens without any unusual adverse effects, and data also are available regarding safety and efficacy of lamivudine in conjunction with zidovudine in children. More limited data are available regarding use of regimens that include stavudine and didanosine, stavudine and lamivudine, or zidovudine and zalcitabine in pediatric patients.

Abacavir, didanosine, lamivudine, stavudine, and zidovudine are labeled by the US Food and Drug Administration (FDA) for use in the treatment of HIV infection in pediatric patients. Zidovudine also is labeled for use in neonates in an attempt to reduce the risk of perinatal transmission of HIV as part of a regimen that includes antepartum and intrapartum zidovudine therapy in the mother and zidovudine therapy in the neonate.

Antiretroviral Therapy in Previously Treated Adults

While zalcitabine has been used in a limited number of childrenand some information is available regarding safety and efficacy of the drug in pediatric patients, zalcitabine is not currently labeled for use in children younger than 13 years of age. Data are accumulating on safety and efficacy of HIV protease inhibitors in pediatric patients. Both nelfinavir and ritonavir are labeled for use in children 2 years of age or older; amprenavir is labeled for use in children 4 years of age or older. Indinavir and saquinavir have been used in HIV-infected children 3 years of age or older, but safety and efficacy of these HIV protease inhibitors in children or adolescents younger than 16 years of age have not been established. Information regarding use of the NNRTIs in children is limited to date.

Nevirapine is labeled for use in pediatric patients 2 months of age or older; efavirenz is labeled for use in children 3 years of age or older; delavirdine is not labeled for use in children younger than 16 years of age.

Initial Antiretroviral Therapy in Treatment-naive Pediatric Patients

The Working Group on Antiviral Therapy and Medical Management of HIV-infected Children recommends aggressive antiretroviral therapy with at least 3 drugs for initial treatment of HIV-infected pediatric patients. The initial antiretroviral regimen selected for infants who were infected perinatally theoretically could be influenced by the antiretroviral regimen their mother may have received during pregnancy, especially if antiretroviral resistance is known or suspected in the mother. However, the Working Group states that currently available data do not suggest that the antiretroviral regimen for infected infants should routinely be chosen based on the regimen used in the mother.

Strongly Recommended Regimens

Based on clinical studies in adults and children, the antiretroviral regimen most strongly recommended for initial therapy in pediatric patients is a 3-drug regimen that includes a highly active HIV protease inhibitor (nelfinavir or ritonavir) and 2 NRTIs (usually zidovudine and didanosine, zidovudine and lamivudine, or stavudine and didanosine; alternatively, stavudine and lamivudine or zidovudine and zalcitabine). A 3-drug regimen that includes efavirenz and 2 NRTIs and a 3-drug regimen of efavirenz, nelfinavir, and one NRTI also are strongly recommended.

Alternative Recommended Regimens

Alternative regimens recommended for initial antiretroviral therapy in pediatric patients include a 3-drug regimen of nevirapine and 2 NRTIs; a 3-drug regimen of abacavir, zidovudine, and lamivudine; a 3-drug regimen of the fixed combination of lopinavir and ritonavir and 2 NRTIs or one NRTI and one NNRTI; or a 3-drug regimen of indinavir or saquinavir (given as liquid-filled [soft gelatin] capsules) and 2 NRTIs. These are considered alternative regimens because durability of suppression of HIV replication may be less than that with strongly recommended regimens (or may not yet be defined), evidence of efficacy may not outweigh potential adverse consequences (toxicity, drug interactions, cost), or experience in infants and children is limited to date.

Antiretroviral Therapy in Previously Treated Adults

Regimens not Recommended

Based on results of clinical trials in children and adults, monotherapy with any antiretroviral agent or a 2-drug regimen of NRTIs are now considered suboptimal regimens for the treatment of HIV-infected children. Use of zidovudine monotherapy is appropriate only in infants younger than 6 weeks of age when the drug is being used for prevention of perinatal transmission of HIV and the HIV status of the infant is indeterminate. If HIV infection is confirmed, the infant should then be switched to a recommended multiple-drug antiretroviral regimen. Although use of a 2-drug regimen of 2 NRTIs may be considered in special circumstances (e.g., when the clinician or guardian/patient has concerns regarding the feasibility of adherence to a more complex antiretroviral regimen), results of studies in adults and children indicate that these 2-drug regimens may be less effective in providing durable suppression of HIV replication than 3-drug regimens that also include an antiretroviral agent from another class.

Because data regarding safety and efficacy of amprenavir in children (especially treatment-naive children) are limited to date, the Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children suggests that use of amprenavir may be considered in previously treated pediatric patients who have failed to respond to regimens that contain other HIV protease inhibitors; however, amprenavir (in conjunction with 2 NRTIs or with abacavir) should be used for initial antiretroviral therapy only in selected pediatric patients and only in special circumstances.

Neonates and Children Younger than 12 Months of Age

The majority of pediatric HIV infections are acquired perinatally, and early identification of HIV-exposed neonates is important in providing effective treatment of these infants. Universal HIV counseling and HIV testing (with consent) of all pregnant women is an important tool in identifying neonates at risk for HIV infection and is recommended as a standard of care for all pregnant women in the US; if maternal HIV serostatus was not determined during the prenatal or immediate postpartum period, diagnostic testing of the infant is recommended.

All infants born to HIV-infected women should receive diagnostic testing to determine if they are HIV infected.Diagnostic testing should be performed within 48 hours of birth and then repeated at 1-2 and 3-6 months of age; repeat testing at 14 days of age in those with a negative result at birth may be advantageous for early detection of infection. Because of improvements in virologic methods used to diagnose HIV infection in infants, a definitive diagnosis can be made in most infected infants by 1 month of age and in virtually all infected infants by 6 months of age. Specific references should be consulted for further information on diagnosis of HIV infection in pediatric patients.

Beginning as soon as possible after delivery (preferably within 8-24 hours after birth) and continued through 6 weeks of life, neonates born to HIV-infected woman should receive the postpartum neonatal component of the zidovudine regimen used to prevent maternal-fetal transmission of HIV. (See Guidelines for Use of Antiretroviral Agents: Antiretrovirals for Prevention of Maternal-fetal Transmission of HIV.) The postpartum neonatal component of the regimen should be administered to the neonate even if the mother failed to receive the antepartum or intrapartum component.

For neonates born to women with a history of prior antiretroviral therapy, some clinicians might consider using a regimen of zidovudine and other antiretroviral agents in the neonate, especially if the mother had disease progression while receiving zidovudine, received extensive prior zidovudine monotherapy, or is infected with HIV-1 with documented high-level zidovudine resistance; however, safety and efficacy of this approach and the most appropriate dosage regimens for these neonates are not completely established. If subsequent diagnostic testing indicates that a neonate receiving zidovudine prophylaxis is HIV infected, the zidovudine regimen should be changed to a multiple-drug antiretroviral regimen recommended for the treatment of pediatric HIV infection. If diagnostic testing for HIV is negative during the first 6 weeks of life, it has been suggested that tests be repeated after completion of the neonatal prophylaxis regimen.

Although there is no evidence that use of zidovudine prophylaxis in the neonate adversely affects or delays neonatal HIV diagnosis, it is unclear whether use of multiple-drug antiretroviral regimens in the mother and/or neonate has any effect on the sensitivity of neonatal virologic diagnostic testing.

Antiretroviral therapy should be initiated in any HIV-infected infant who is symptomatic or has evidence of immunosuppression, regardless of age or plasma HIV-1 RNA level. Because HIV-infected infants younger than 12 months of age are at high risk for disease progression, the Working Group states that, ideally, antiretroviral therapy should be initiated in this age group immediately after the diagnosis, regardless of clinical or immunologic status or viral load.

However, definitive clinical studies documenting therapeutic benefit from this approach are not available and the choice of appropriate antiretroviral regimens in this age group is complicated by the fact that data are limited to date regarding dosage regimens of many antiretroviral agents for use in children younger than 6 months. In addition, issues related to adherence should be fully assessed and discussed with caregivers of asymptomatic HIV-infected infants before a decision to initiate antiretroviral therapy is made.

Children 12 Months of Age or Older

Antiretroviral therapy should be initiated in any HIV-infected adolescent or child who is symptomatic or has evidence of immunosuppression, regardless of age or plasma HIV-1 RNA levels. For asymptomatic children 12 months of age or older without evidence of immunosuppression, there are 2 general approaches to initiating therapy that can be considered. The first approach is therapeutically more aggressive and involves initiating antiretroviral therapy regardless of age or symptom status.

The alternative approach is to defer initiation of antiretroviral therapy in asymptomatic children 12 months of age or older who have normal immune status in situations in which the risk for clinical disease progression is low (e.g., low viral load) and when other factors (e.g., concern for the durability of response, safety, and adherence) favor postponing treatment. In such cases, virologic, immunologic, and clinical status of the child should be monitored regularly and therapy should be initiated if clinical symptoms develop, plasma HIV-1 RNA levels are high or increasing, or CD4+ T-cell counts or percentages rapidly decline and approach those indicating moderate immunosuppression. The level of plasma HIV-1 RNA considered indicative of increased risk for disease progression is not well defined for young children.

However, any child (regardless of age) who has plasma HIV-1 RNA levels exceeding 100,000 copies/mL is at high risk for mortality and should receive antiretroviral therapy. In older children (30 months of age or older), the risk of disease progression or death at 2 years of follow-up is very low when plasma HIV-1 RNA levels are 15,000 copies/mL or less, but the risk increases to 13% or higher when HIV-1 RNA levels are higher.

The Working Group recommends that antiretroviral therapy be offered (regardless of clinical or immunologic status or absolute level of viral load) to any child with a plasma HIV-1 RNA level that increases substantially (more than a fivefold increase for children younger than 2 years of age or more than a threefold increase for those 2 years of age or older) on repeated testing, provided there are no possible alternative causes for transient increases in these levels (e.g., concurrent vaccination or infection).

Adolescents

Currently, most HIV-infected adolescents were infected sexually during the adolescent period and are in a relatively early stage of infection. Adolescents infected with HIV through sexual exposure or IV drug use during adolescence generally experience a clinical course that is similar to that of adults, and such adolescents are treated most appropriately using the guidelines recommended for adults. There are, however, a growing number of adolescents who were either infected perinatally or as young children through HIV-infected blood products and such adolescents may have a unique clinical course that differs from other adolescents or those infected later in life.

When antiretroviral therapy is initiated in an adolescent, consideration should be given to the possibility that physiologic changes that occur at the time of puberty may affect the pharmacokinetics of the various antiretroviral agents and theoretically could impact efficacy of the drugs.

Experience to date using NRTIs in adolescents has not revealed evidence of such an effect with these agents; however, experience is limited to date using HIV protease inhibitors and NNRTIs in adolescents. Therefore, the Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children and other clinicians recommend that dosage of antiretroviral agents be based on Tanner staging of puberty rather than age.

These clinicians suggest that adolescents in early puberty (Tanner I-II) are most appropriately treated using pediatric guidelines and dosages and that those in late puberty (Tanner V) are most appropriately treated using adult guidelines and dosages. Those in the middle of their growth spurts (Tanner III in females and Tanner IV in males) should be monitored closely for antiretroviral agent efficacy and toxicity when choosing between adult and pediatric guidelines.

Subscribe
Notify of
0 Comments
Inline Feedbacks
View all comments