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PHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
  Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents PDF format
Excerpts from new Updated PHHS HIV Treatment Guidelines.
Developed by the panel on Clinical Practices for Treatment of HIV Infection convened by the Developed by the Panel on Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services (DHHS).
It is emphasized that concepts relevant to HIV management evolve rapidly. The Panel has a mechanism to update recommendations on a regular basis, and the most recent information is available on the AIDSinfo Web site (http://AIDSinfo.nih.gov).
-Viral load testing
-Drug resistance testing
-Recommended Combination Antiretroviral Regimens
-Interruption of Antiretroviral Therapy
Antiretroviral regimens are complex, have serious side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance because of nonadherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic decisions is critical. Treatment should usually be offered to all patients with symptoms ascribed to HIV infection. Recommendations for offering antiretroviral therapy among asymptomatic patients require analysis of real and potential risks and benefits. Treatment should be offered to persons who have <350 CD4 + T cells/mm 3 or plasma HIV ribonucleic acid (RNA) levels of >55,000 copies/mL (by b-deoxyribonucleic acid [bDNA] or reverse transcriptase-polymerase chain reaction [RT-PCR] assays). The recommendation to treat asymptomatic patients should be based on the willingness and readiness of the person to begin therapy; the degree of existing immunodeficiency as determined by the CD4 + T cell count; the risk for disease progression as determined by the CD4 + T cell count and level of plasma HIV RNA; the potential benefits and risks of initiating therapy in an asymptomatic person; and the likelihood, after counseling and education, of adherence to the prescribed treatment regimen.
Treatment goals should be maximal and durable suppression of viral load, restoration and preservation of immunologic function, improvement of quality of life, and reduction of HIV-related morbidity and mortality. Results of therapy are evaluated through plasma HIV RNA levels, which are expected to indicate a 1.0 log10 decrease at 2-8 weeks and no detectable virus (<50 copies/mL) at 4-6 months after treatment initiation. Failure of therapy at 4-6 months might be ascribed to nonadherence, inadequate potency of drugs or suboptimal levels of antiretroviral agents, viral resistance, and other factors that are poorly understood. Patients whose therapy fails in spite of a high level of adherence to the regimen should have their regimen changed; this change should be guided by a thorough drug treatment history and the results of drug-resistance testing. Because of limitations in the available alternative antiretroviral regimens that have documented efficacy, optimal changes in therapy might be difficult to achieve for patients in whom the preferred regimen has failed. These decisions are further confounded by problems with adherence, toxicity, and resistance. For certain patients, participating in a clinical trial with or without access to new drugs or using a regimen that might not achieve complete suppression of viral replication might be preferable. Because concepts regarding HIV management are evolving rapidly, readers should check regularly for additional information and updates.
Three HIV viral load assays have been approved by the Food and Drug Administration (FDA) for determining prognosis and for monitoring the response to therapy. These include:
1. the HIV-1 reverse transcriptase polymerase chain reaction assay (Amplicor HIV-1 Monitor Test, version 1.5, Roche Diagnostic),
2. in vitro nucleic amplification test for HIV-RNA (NucliSens HIV-1 QT, Organon Teknika), and
3. in vitro signal amplification nucleic acid probe assay [VERSANT HIV-1 RNA 3.0 Assay (bDNA)].
The former two assays were approved for a lower limit of detection at 50 copies/mL, where the approved lower limit of detection for the bDNA assay was 75 copies/mL. Because there are significant variability in the techniques and quantitative measurements among the three assays, clinicians are advised to use the same assay in monitoring the plasma viral load responses for an individual patient. Multiple analyses among >5,000 patients who participated in approximately 18 trials with viral load monitoring indicated a statistically significant dose-response-type association between decreases in plasma viremia and improved clinical outcome on the basis of standard results of new AIDS-defining diagnoses and survival. This relationship was observed throughout a range of patient baseline characteristics, including pretreatment plasma RNA level, CD4 + T cell count, and previous drug experience.
Thus, viral load testing is an essential parameter in deciding to initiate or change antiretroviral therapies. Measurement of plasma HIV RNA levels (i.e., viral load) by using quantitative methods should be performed at the time of diagnosis and every 3-4 months thereafter for the untreated patient. CD4 + T cell counts should be measured at the time of diagnosis and every 3-6 months thereafter. These intervals between tests are recommendations only, and flexibility should be exercised according to the circumstances of each
Plasma HIV RNA levels should also be measured immediately before and again at 2-8 weeks after initiation of antiretroviral therapy. This second measurement allows the clinician to evaluate initial therapy effectiveness because, for the majority of patients, adherence to a regimen of potent antiretroviral agents should result in a substantial decrease (~1.0 log10) in viral load by 2-8 weeks. A patient's viral load should continue to decline during the following weeks and, for the majority of patients, should decrease below detectable levels (i.e., defined as <50 RNA copies/mL by the Amplicor HIV-1 Monitor test or Nuclisens assay; or < 75 copies/mL by VERSANT HIV-1 RNA 3.0 Assay) by 16-24 weeks. Rates of viral load decline below the limit of detection are affected by the baseline CD4 + T cell count, the initial viral load, potency of the regimen, adherence to the regimen, previous exposure to antiretroviral agents, and the presence of any OIs.
These differences must be considered when monitoring the effect of therapy. However, the absence of a virologic response of the magnitude discussed previously should prompt the clinician to reassess patient adherence, rule out malabsorption or drug interactions, consider repeat RNA testing to document lack of response, or consider a change in drug regimen. After the patient is on therapy, HIV RNA testing should be repeated every 3-4 months to evaluate the continuing effectiveness of therapy. With optimal therapy, viral levels in plasma at 24 weeks should be below the limit of detection. Data from clinical trials demonstrate that lowering plasma HIV RNA to <50 copies/mL (or <75 copies/mL by VERSANT HIV-1 RNA 3.0 Assay) is associated with increased duration of viral suppression, compared with reducing HIV RNA to levels of 50-500 copies/mL. If HIV RNA remains detectable in plasma after 16-24 weeks of therapy, the plasma HIV RNA test should be repeated to confirm the result and a change in therapy should be considered.
A minimal change in plasma viremia is considered to be a threefold or 0.5-log10 increase or decrease. A substantial decrease in CD4 + T lymphocyte count is a decrease of >30% from baseline for absolute cell numbers and a decrease of >3% from baseline in percentages of cells. Discordance between trends in CD4 + T cell numbers and plasma HIV RNA levels was documented among 20% of patients in one cohort studied. Such discordance can complicate decisions regarding antiretroviral therapy and might be caused by factors that affect plasma HIV RNA testing. Viral load and trends in viral load are believed to be more informative for decision-making regarding antiretroviral therapy than are CD4 + T cell counts; however, exceptions to this rule do occur. In certain situations, consultation with a specialist should be considered.
Genotyping assays detect drug resistance mutations that are present in the relevant viral genes (i.e., reverse transcriptase and protease). Certain genotyping assays involve sequencing of the entire reverse transcriptase and protease genes, whereas others use probes to detect selected mutations that are known to confer drug resistance. Genotyping assays can be performed rapidly, and results can be reported within 1-2 weeks of of sample collection. Interpretation of test results requires knowledge of the mutations that are selected for by different antiretroviral drugs and of the potential for cross-resistance to other drugs conferred by certain mutations. The IAS-USA maintains a list of significant resistance-associated mutations in the reverse transcriptase, protease, and envelope genes (see www.iasusa.org/resistance_mutations). Various techniques such as rules-based algorithms and "virtual phenotype" are now available to assist the provider in interpreting genotyping test results. Consultation with a specialist in HIV drug resistance is encouraged and can facilitate interpretation of genotyping results; the benefit of such consultation has been demonstrated.
Phenotyping assays measure a virus's ability to grow in different concentrations of antiretroviral drugs. Automated, recombinant phenotyping assays are commercially available with results available in 2-3 weeks; however, phenotyping assays are more costly to perform than genotyping assays. Recombinant phenotyping assays involve insertion of the reverse transcriptase and protease gene sequences derived from patient plasma HIV RNA into the backbone of a laboratory clone of HIV either by cloning or by in vitro recombination. Replication of the recombinant virus at different drug concentrations is monitored by expression of a reporter gene and is compared with replication of a reference HIV strain. Drug concentrations that inhibit 50% and 90% of viral replication (i.e., the median inhibitory concentration [IC] IC50 and IC90) are calculated, and the ratio of the IC50 of test and reference viruses is reported as the fold increase in IC50 (i.e., fold resistance). Interpretation of phenotyping assay results is complicated by the paucity of data regarding the specific resistance level (i.e., fold increase in IC50) that is associated with drug failure, although clinically significant fold increase cutoffs are now available for some drugs. Again, consultation with a specialist can be helpful for interpreting test results.
Further limitations of both genotyping and phenotyping assays include the lack of uniform quality assurance for all available assays, relatively high cost, and insensitivity for minor viral species. If drug-resistant viruses are present but constitute <10%-20% of the circulating virus population, they probably will not be detected by available assays. This limitation is critical when interpreting data regarding susceptibility to drugs that the patient has taken in the past but that are not part of the current antiretroviral regimen. If drug resistance had developed to a drug that was subsequently discontinued, the drug-resistant virus can become a minor species because its growth advantage is lost. Consequently, resistance assays should be performed while the patient is taking his or her antiretroviral regimen, and data suggesting the absence of resistance should be interpreted cautiously in relation to the previous treatment history.
Transmission of drug-resistant HIV strains has been documented and has been associated with a suboptimal virologic response to initial antiretroviral therapy.
If the decision is made to initiate therapy in a person with acute HIV infection, it is likely that resistance testing at baseline will optimize virologic response, although this strategy has not been tested in prospective clinical trials. Because of its more rapid turnaround time, using a genotyping assay might be preferred in this situation. Since some resistance-associated mutations are known to persist in the absence of drug pressure, it may be reasonable to extend this strategy for 1-2 years post-seroconversion. Using resistance testing before initiation of antiretroviral therapy in patients with chronic HIV infection is less straightforward. Available resistance assays might fail to detect drug-resistant species that were transmitted when primary infection occurred but, with the passage of time, became a minor species in the absence of selective drug pressure. As with acute HIV infection, prospective evaluation of "baseline" resistance testing in this setting has not been performed. It may be reasonable to consider such testing, however, when there is a significant probability that the patient was infected with a drug-resistance virus, i.e., if the patient is thought to have been infected by a person who was receiving antiretroviral drugs. A recent study suggested that baseline testing may be cost-effective when the prevalence of drug resistance in the relevant drug-naive population is >5%, but such data are infrequently available.
In pregnant women, the purpose of antiretroviral therapy is to reduce HIV plasma RNA to below the limit of detection, for the benefit of both mother and child. In this regard, recommendations for resistance testing during pregnancy are the same as for nonpregnant persons.
The Panel lists two preferred first-line regimens, a PI and an NNRTI.
Nonnucleoside Reverse Transcriptase Inhibitor-Based Regimens The Panel recommends:
--Efavirenz in combination with (zidovudine or tenofovir or stavudine) plus lamivudine as preferred initial NNRTI-based regimens (except for pregnant women).
Protease Inhibitor-Based Regimen
The Panel recommends:
--Kaletra (lopinavir/ritonavir) in combination with (zidovudine or stavudine) plus lamivudine as preferred PI-based regimens. Alternative PI-based regimens are listed.
Triple NRTI Regimen
The Panel recommends that a 3-NRTI regimen consisting of abacavir + (zidovudine or stavudine) + lamivudine may be used as an alternative to an NNRTI-based or a PI-based regimen in antiretroviral-naive patients. This regimen should not be initiated in patients with baseline viral load >100,000 copies/mL.
Efavirenz- vs Nevirapine-Based Regimens
Two studies have compared the efficacy and tolerability of nevirapine with efavirenz. In one small study, after 48 weeks, 64% of 36 patients assigned to nevirapine and 74% of 31 patients assigned to efavirenz, each with d4T+ddI, had a viral load <50 copies/mL. The 95% CI for the difference (-32% to 12%) was too wide to draw meaningful conclusions about the similarity (or lack thereof) of efficacy.
The 2NN study was a large study that compared nevirapine with efavirenz, in antiretroviral naive participants. Patients were randomized to nevirapine (400 mg once daily or qd; n= 220), nevirapine (200 mg twice daily or bid; n= 387), efavirenz (600 mg qd; n=400), or nevirapine (400 mg qd) plus efavirenz (800 mg qd) (n=209), together with d4T+3TC.
Treatment failure at 48 weeks was defined as less than one log10 decline in the first 12 weeks, virologic failure from week 24 onward (two consecutive viral load measurements >50 copies/mL), switch from assigned treatment drugs, or progression to death or CDC category C event. Secondary outcomes included percent with viral load <50 copies/mL at 48 weeks, changes in CD4 + T-lymphocyte cell count, changes in lipid levels, and adverse events. At 48 weeks, 43.7% of patients in the bid nevirapine arm and 37.8% of those in the efavirenz arm experienced treatment failure (95% CI for difference: -0.9 to 12.8%; p=0.095). At this same time point, 65.4% of patients in the bid nevirapine arm and 70.0% of those in the efavirenz arm had viral load <50 copies/mL (95% CI for difference: -1.9% to 11.2%; p=0.17). The CD4+ cell count increase was the same in both groups (160 cells/mm 3).
The percent of patients discontinuing treatment due to an adverse event was 21.2% in the bid nevirapine group and 15.5% in efavirenz group (95% CI: 0.3% to 11.1%; p = 0.04). More patients on bid nevirapine than efavirenz experienced a grade 3/4 clinical hepatotoxicity (2.1% versus 0.3%) and a grade 3/4 laboratory hepatobiliary toxicity (7.8% versus 4.5%). Of note, two deaths (due to toxic hepatitis and Steven's-Johnson syndrome) were attributed to bid nevirapine in this study. Other notable findings from this study are that qd nevirapine was similar in efficacy to bid nevirapine (43.6% versus 43.7% for treatment failure outcome) although more laboratory hepatotoxicities were found with the once-daily than with the twice-daily dose (13.2% versus 7.8%). The combination of nevirapine and efavirenz resulted in a discontinuation rate due to adverse events of 29.7%.
In the design of the 2NN study, a difference between the two treatment groups of 10% in treatment failure at 48 weeks was prespecified to be clinically meaningful. The results of the study indicate that a difference of this magnitude cannot be ruled out (i.e., based on the upper bound of the 95% confidence interval, the advantage of efavirenz over nevirapine at 48 weeks may exceed 10% for major efficacy outcomes). Furthermore, there appears to be more safety concerns (particularly, higher incidence and more serious skin rash and hepatotoxicity) about using nevirapine over efavirenz.
On the basis of the clinical trial results as discussed above, the Panel recommends efavirenz in combination with lamivudine and zidovudine, tenofovir, or stavudine as preferred first-line NNRTI-containing regimens in antiretroviral naive patients. An exception to this recommendation will be in pregnant women or women at risk for pregnancy, as efavirenz has been associated with significant teratogenic effects in nonhuman primates.
Protease Inhibitor-Based Regimen
The largest of the studies evaluating a low-dose ritonavir-boosted regimen is a trial of lopinavir/ritonavir versus nelfinavir (each with 2 NRTIs) involving 653 patients. In this trial 400 mg of lopinavir and 100 mg of ritonavir (as a co-formulated preparation) given twice daily was well tolerated and was superior to nelfinavir (750 mg thrice daily) in maintaining a viral load <400 copies/mL through 48 weeks (84% versus 66% with persistent virologic response through 48 weeks; hazard ratio = 2.0; 95% CI: 1.5 to 2.7). Overall adverse event rates and study discontinuation rates due to adverse events were similar in the two groups, although average triglycerides elevations were greater among those assigned lopinavir/ritonavir compared to nelfinavir (125 mg/dl versus 47 mg/dl increase; p<0.001).
Antiretroviral therapy might need to be discontinued temporarily or permanently for multiple reasons. If a need exists to discontinue any antiretroviral medication, clinicians and patients should be aware of the theoretical advantage of stopping all antiretroviral agents simultaneously, rather than continuing one or two agents, to minimize the emergence of resistant viral strains. If a decision is made to interrupt therapy, the patient should be monitored closely, including clinical and laboratory evaluations. Chemoprophylaxis against OIs should be initiated as needed on the basis of CD4+ T cell count.
An interest exists in what is sometimes referred to as structured or supervised treatment interruptions (STI). The concepts underlying STI vary, depending on patient populations, and encompass more than 3 major strategies:
1. STI as part of salvage therapy;
2. STI for autoimmunization and improved immune control of HIV; and
3. STI for the sole purpose of allowing less total time on antiretroviral therapy.
Because of limited available data, none of these approaches can be recommended.
Salvage STI is intended for patients whose virus has developed substantial antiretroviral drug resistance and who have persistent plasma viremia and relatively low CD4 + T cell counts despite receiving therapy. The theoretical goal of STI in this patient population is to allow for the reemergence of HIV that is susceptible to antiretroviral therapy. Although HIV that was sensitive to antiretroviral agents was detected in the plasma of persons after weeks or months of interrupted treatment, the emergence of drug-sensitive HIV was associated with a substantial decline in CD4 + T cells and a substantial increase in plasma viremia, indicating improved replicative fitness and pathogenicity of wild type virus. In addition, drug-resistant HIV persisted in CD4 + T cells. The observed decrease in CD4 + T cells is of concern in this patient population, and STI cannot be recommended for these patients.
Autoimmunization STI and STI for the reduction of total time receiving antiretroviral drugs are intended for persons who have maintained suppression of plasma viremia below the limit of detection for prolonged periods of time and who have relatively high CD4 + T cell counts. The theoretical goal of autoimmunization STI is to allow multiple short bursts of viral replication to augment HIV-specific immune responses. This strategy is being studied among persons who began HAART during either the very early stage or chronic stages of HIV infection. STI for the purpose of spending less time on therapy employs predetermined periods of long- or short-cycle intermittent antiretroviral therapy. The numbers of patients and duration of follow-up are insufficient for adequate evaluation of these approaches. Risks include a decline in CD4 + T cell counts, an increase in transmission, and the development of drug resistance.
Because of insufficient data regarding these situations, STI cannot be recommended for use in general clinical practice. Further research is necessary in each of these areas. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents PDF format
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