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Clinical Guidelines |

Guidelines for Using Antiretroviral Agents among HIV-Infected Adults and Adolescents: The Panel on Clinical Practices for Treatment of HIV* FREE

Mark Dybul, MD; Anthony S. Fauci, MD; John G. Bartlett, MD; Jonathan E. Kaplan, MD; and Alice K. Pau, PharmD
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This document was originally published in MMWR on 14 June 2002 (RR81).


Ann Intern Med. 2002;137(5_Part_2):381-433. doi:10.7326/0003-4819-137-5_Part_2-200209031-00001
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This report was developed by the Panel on Clinical Practices for Treatment of HIV (the Panel), which was convened by the Department of Health and Human Services (DHHS) and the Henry J. Kaiser Family Foundation in 1996. The goal of these recommendations is to provide evidence-based guidance for clinicians and other health-care providers who use antiretroviral agents in treating adults and adolescents† infected with human immunodeficiency virus (HIV), including pregnant women. Although the pathogenesis of HIV infection and the general virologic and immunologic principles underlying the use of antiretroviral therapy are similar for all HIV-infected persons, unique therapeutic and management considerations exist for HIV-infected children. Therefore, guidance for antiretroviral therapy for pediatric HIV infection is not contained in this report. A separate report addresses pediatric-specific concerns related to antiretroviral therapy and is available at http://www.hivatis.org.

These guidelines serve as a companion to the therapeutic principles from the National Institutes of Health (NIH) Panel To Define Principles of Therapy of HIV Infection (1). Together, the reports provide pathogenesis-based rationale for therapeutic strategies as well as guidelines for implementing these strategies. Although the guidelines represent the state of knowledge regarding the use of antiretroviral agents, this is an evolving science and the availability of new agents or new clinical data regarding the use of existing agents will change therapeutic options and preferences. Because this report needs to be updated periodically, a subgroup of the Panel on Clinical Practices for Treatment of HIV Infection, the Antiretroviral Working Group, meets monthly to review new data. Recommendations for changes are then submitted to the Panel and incorporated as appropriate. §These recommendations are not intended to supersede the judgment of clinicians who are knowledgeable in the care of HIV-infected persons. Furthermore, the Panel recommends that, when possible, the treatment of HIV-infected patients should be directed by a clinician who has extensive experience in the care of these patients. When this is not possible, the patient should have access to such clinical experience through consultations.

Each recommendation is accompanied by a rating that includes a letter and a Roman numeral (Table 1) and is similar to the rating schemes used in previous guidelines concerning prophylaxis of opportunistic infections (OIs) issued by the U.S. Public Health Service and the Infectious Diseases Society of America (2). The letter indicates the strength of the recommendation, which is based on the opinion of the Panel, and the Roman numeral reflects the nature of the evidence supporting the recommendation (Table 1). Thus, recommendations made on the basis of data from clinical trials with clinical results are differentiated from those made on the basis of laboratory results (e.g., CD4+ T lymphocyte count or plasma HIV ribonucleic acid [RNA] levels). When clinical trial data are unavailable, recommendations are made on the basis of the opinions of persons experienced in the treatment of HIV infection and familiar with the relevant literature.

Table Jump PlaceholderTable 1.  Rating Scheme for Clinical Practice Recommendations

Decisions regarding initiation or changes in antiretroviral therapy should be guided by monitoring the laboratory parameters of plasma HIV RNA (viral load) and CD4+ T cell count in addition to the patient's clinical condition. Results of these laboratory tests provide clinicians with key information regarding the virologic and immunologic status of the patient and the risk for disease progression to acquired immunodeficiency syndrome (AIDS) (34). HIV viral load testing has been approved by the Food and Drug Administration (FDA) for determining prognosis and for monitoring the response to therapy only for the reverse transcriptase-polymerase chain reaction (RT-PCR) assay and in vitro nucleic amplification test for HIV–RNA (NucliSens® HIV-1 QT, manufactured by Organon Teknika). Multiple analyses among >5000 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 (AIII) (Table 2). CD4+ T cell counts should be measured at the time of diagnosis and every 3–6 months thereafter (AIII). These intervals between tests are recommendations only, and flexibility should be exercised according to the circumstances of each patient. Plasma HIV RNA levels should also be measured immediately before and again at 2–8 weeks after initiation of antiretroviral therapy (AIII). 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 of plasma) by 16–24 weeks. Rates of viral load decline toward undetectable 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, consider repeat RNA testing to document lack of response, or consider a change in drug regimen. After the patient is receiving therapy, HIV RNA testing should be repeated every 3–4 months to evaluate the continuing effectiveness of therapy (AII). With optimal therapy, viral levels in plasma at 24 weeks should be undetectable (5). Data from clinical trials demonstrate that lowering plasma HIV RNA to <50 copies/mL is associated with increased duration of viral suppression, compared with reducing HIV RNA to levels of 50–500 copies/mL (6). 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 (see Changing a Failing Regimen) (BIII).

Table Jump PlaceholderTable 2.  Indications for Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) Testing

When deciding on therapy initiation, the CD4+ T lymphocyte count and plasma HIV RNA measurement should be performed twice to ensure accuracy and consistency of measurement (BIII). However, among patients with advanced HIV disease, antiretroviral therapy should be initiated after the first viral load measurement is obtained to prevent a potentially deleterious delay in treatment. The requirement for two measurements of viral load might place a substantial financial burden on patients or payers. Nonetheless, the Panel believes that two measurements of viral load will provide the clinician with the best information for subsequent patient follow-up. Plasma HIV RNA levels should not be measured during or within 4 weeks after successful treatment of any intercurrent infection, resolution of symptomatic illness, or immunization. Because differences exist among commercially available tests, confirmatory plasma HIV RNA levels should be measured by using the same laboratory and the same technique to ensure consistent results.

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 (7). Discordance between trends in CD4+ T cell numbers and plasma HIV RNA levels was documented among 20% of patients in one cohort studied (8). 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 (see Changing a Failing Regimen). In certain situations, consultation with a specialist should be considered.

Testing for HIV resistance to antiretroviral drugs is a useful tool for guiding antiretroviral therapy. When combined with a detailed drug history and efforts in maximizing drug adherence, these assays might maximize the benefits of antiretroviral therapy. Studies of treatment-experienced patients have reported strong associations between the presence of drug resistance, identified by genotyping or phenotyping resistance assays, and failure of the antiretroviral treatment regimen to suppress HIV replication. 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 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. Consultation with a specialist in HIV drug resistance is encouraged and can facilitate interpretation of genotypic test results.

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, compared with genotypic 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 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 the 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; 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 (9). Consequently, resistance assays should be performed while the patient is taking his or her antiretroviral regimen, and data substantiating the absence of resistance should be interpreted cautiously in relation to the previous treatment history.

Resistance assays can be useful for patients experiencing virologic failure while on antiretroviral therapy and patients with acute HIV infection (Table 3). Recent prospective data supporting drug-resistance testing in clinical practice are derived from trials in which the test utility was assessed for cases of virologic failure. Two studies compared virologic responses to antiretroviral treatment regimens when genotyping resistance tests were available to guide therapy (1011) with the responses observed when changes in therapy were guided by clinical judgment only. The results of both studies indicated that the short-term virologic response to therapy was substantially increased when results of resistance testing were available. Similarly, a prospective, randomized, multicenter trial demonstrated that therapy selected on the basis of phenotypic resistance testing substantially improves the virologic response to antiretroviral therapy, compared with therapy selected without the aid of phenotypic testing (12). Thus, resistance testing appears to be a useful tool in selecting active drugs when changing antiretroviral regimens in cases of virologic failure (BII). Similar rationale applies to the potential use of resistance testing for patients with suboptimal viral load reduction (see Criteria for Changing Therapy) (BIII). Virologic failure regarding highly active antiretroviral therapy (HAART) is, for certain patients, associated with resistance to one component of the regimen only (13); in that situation, substituting individual drugs in a failing regimen might be possible, although this concept requires clinical validation (see Changing a Failing Regimen). No prospective data exist to support using one type of resistance assay over another (i.e., genotyping versus phenotyping) in different clinical situations. Therefore, one type of assay is recommended per sample; however, for patients with a complex treatment history, both assays might provide critical and complementary information.

Table Jump PlaceholderTable 3.  Recommendations for Using Drug-Resistance Assays

Transmission of drug-resistant HIV strains has been documented and might be associated with a suboptimal virologic response to initial antiretroviral therapy (1417). If the decision is made to initiate therapy in a person with acute HIV infection, using resistance testing to optimize the initial antiretroviral regimen is a reasonable, albeit untested, strategy (1819) (CIII). Because of its more rapid turnaround time, using a genotypic assay might be preferred in this situation. Using resistance testing before initiation of antiretroviral therapy among patients with chronic HIV infection is not recommended (DIII) because of uncertainty regarding the prevalence of resistance among treatment-naïve persons. In addition, available resistance assays might fail to detect drug-resistant species that were transmitted when primary infection occurred but became a minor species in the absence of selective drug pressure. Reserving resistance testing for patients with suboptimal viral load suppression after therapy initiation is preferable, although this approach might change as additional information becomes available related to the prevalence of resistant virus among antiretroviral-naïve patients.

Recommendations for resistance testing during pregnancy are the same as for nonpregnant women; acute HIV infection, virologic failure while on an antiretroviral regimen, or suboptimal viral load suppression after initiation of antiretroviral therapy are all appropriate indications for resistance testing. If an HIV-positive pregnant woman is taking an antiretroviral regimen that does not include zidovudine, or if zidovudine was discontinued because of maternal drug resistance, intrapartum and neonatal zidovudine prophylaxis should be administered to prevent mother-to-child HIV transmission (see Considerations for Antiretroviral Therapy Among HIV-Infected Pregnant Women). Not all of zidovudine's activity in preventing mother-to-child HIV transmission can be accounted for by its effect on maternal viral load (20); furthermore, preliminary data indicate that the rate of perinatal transmission after zidovudine prophylaxis might not differ between those with and without zidovudine-resistance mutations (2122). Studies are needed to determine the best strategy to prevent mother-to-child HIV transmission in the presence of zidovudine resistance.

Patients with established HIV infection are discussed in two arbitrarily defined clinical categories: asymptomatic infection or symptomatic disease (e.g., wasting, thrush, or unexplained fever for >2 weeks) including AIDS, as classified by CDC in 1993 (23). All patients in the second category should be offered antiretroviral therapy. Initiating antiretroviral therapy among patients in the first category is complex and, therefore, discussed separately. However, before initiating therapy for any patient, the following evaluation should be performed:

  • complete history and physical (AII);

  • complete blood count, chemistry profile, including serum transaminases and lipid profile (AII);

  • CD4+ T lymphocyte count (AI); and

  • plasma HIV RNA measurement (AI).

Additional evaluation should include routine tests relevant to preventing OIs, if not already performed (e.g., rapid plasma reagin or Venereal Disease Research Laboratory test; tuberculin skin test; toxoplasma immunoglobulin G serology; hepatitis B and C serology; and gynecologic exam, including Papanicolaou smear). Other tests are recommended, if clinically indicated (e.g., chest radiograph and ophthalmologic exam) (AII). Cytomegalovirus serology can be useful for certain patients (2) (BIII).

Although randomized clinical trials provide strong evidence for treating patients with <200 CD4+ T cells/mm3(2426), the optimal time to initiate antiretroviral therapy among asymptomatic patients with CD4+ T cell counts >200 cells/mm3 is unknown. For persons with >200 CD4+ T cells/mm3, the strength of the recommendation for therapy must balance the readiness of the patient for treatment, consideration of the prognosis for disease-free survival as determined by baseline CD4+ T cell count and viral load levels, and assessment of the risks and potential benefits associated with initiating antiretroviral therapy.

Regarding a prognosis that is based on the patient's CD4+ T cell count and viral load, data are absent concerning clinical endpoints from randomized, controlled trials for persons with >200 CD4+ T cells/mm3 to guide decisions on when to initiate therapy. However, despite their limitations, observational cohorts of HIV-infected persons either treated or untreated with antiretroviral therapy provide key data to assist in risk assessment for disease progression.

Observational cohorts have provided critical data regarding the prognostic influence of viral load and CD4+ T cell count in the absence of treatment. These data indicate a strong relationship between plasma HIV RNA levels and CD4+ T cell counts in terms of risk for progression to AIDS for untreated persons and provide potent support for the conclusion that therapy should be initiated before the CD4+ T cell count declines to <200 cells/mm3 (Figure; Tables 4 and 5). In addition, these studies are useful for the identification of asymptomatic persons at high risk who have CD4+ T cell counts >200 cells/mm3 and who might be candidates for antiretroviral therapy or more frequent CD4+ T cell count monitoring. Regarding CD4+ T cell count monitoring, the Multicenter AIDS Cohort Study (MACS) demonstrated that the 3-year risk for progression to AIDS was 38.5% among patients with 201–350 CD4+ T cells/mm3, compared with 14.3% for patients with CD4+ T cell counts >350 cells/mm3. However, the short-term risk for progression also was related to the level of plasma HIV RNA, and the risk was relatively low for those persons with <20,000 copies/mL. An evaluation of 231 persons with CD4+ T cell counts of 201–350 cells/mm3 demonstrated that the 3-year risk for progression to AIDS was 4.1% for the 74 patients with HIV RNA <20,000; 36.4% for those 53 patients with HIV RNA 20,001–55,000 copies/mL; and 64.4% for those 104 patients with HIV RNA >55,000 copies/mL. Similar risk gradations by viral load were evident for patients with CD4+ T cell counts >350 cells/mm3 (Figure; Table 5) (unpublished data, Alvaro Muñoz, PhD, Johns Hopkins University, Baltimore, Maryland, 2001). These data indicate that for certain patients with CD4+ T cell counts >200 cells/mm3, the 3-year risk for disease progression to AIDS in the absence of treatment is substantially increased. Thus, although observational studies of untreated persons cannot assess the effects of therapy and, therefore, cannot determine the optimal time to initiate therapy, these studies do provide key guidance regarding the risks for progression in the absence of therapy on the basis of a patient's CD4+ T cell count and viral load.

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Figure.
Likelihood of developing AIDS by 3 years after becoming infected with HIV.

*b-Deoxyribonucleic acid; †reverse transcriptase-polymerase chain reaction. Source: Mellors JW, Muñoz A, Gigorni JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med. 1997;126:946-54.

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Table Jump PlaceholderTable 4.  Risks and Benefits of Delayed Versus Early Therapy Initiation for the Asymptomatic Human Immunodeficiency Virus (HIV)-Infected Patient
Table Jump PlaceholderTable 5.  Risk for Progression to Acquired Immunodeficiency Syndrome (AIDS)-Defining Illness among a Cohort of Men Who Have Sex with Men, Predicted by Baseline CD4+ T Cell Count and Viral Load

Data from observational studies of HAART-treated cohorts also provide critical information to guide using antiretroviral therapy among asymptomatic patients (2730). A collaborative analysis of data from 13 cohort studies from Europe and North America demonstrates that among drug-naïve patients without AIDS-defining illness and a viral load of <100,000 copies/mL, the 3-year probability of progression to AIDS or death was 15.8% among those who initiated therapy with CD4+ T cell counts of 0–49 cells/mm3; 12.5% among those with CD4+ T cell counts of 50–99 cells/mm3; 9.3% among those with CD4+ T cell counts of 100–199 cells/mm3; 4.7% among those with CD4+ T cell counts of 200–349 cells/mm3; and 3.4% among those with CD4+ T cell counts of 350 cells/mm3 or higher (30). These data indicate that the prognosis might be better for patients who initiate therapy at >200 cells/mm3; but risk after initiation of therapy does not vary considerably at >200 cells/mm3. However, risk for progression also was related to plasma HIV RNA levels in this study. A substantial increase in risk for progression was evident among all patients with a viral load >100,000 copies/mL. In other cohort studies, an apparent benefit in terms of disease progression was reported among persons who began antiretroviral therapy when CD4+ T cell counts were >350 cells/mm3, compared with those who deferred therapy (3132). For example, in the Swiss cohort study, an approximate 7-fold decrease occurred in disease progression to AIDS among persons who initiated therapy with a CD4+ T cell count >350 cells/mm3, compared with those who were monitored without therapy during a 2-year period (32). However, a substantial incidence of adverse treatment effects occurred among patients who initiated therapy; 40% of patients had ≥ 1 treatment changes because of adverse effects, and 20% were no longer receiving treatment after 2 years (32). Unfortunately, observational studies of persons treated with HAART also have limitations regarding the ability to determine an optimal time to initiate therapy. The relative risks for disease progression for persons with CD4+ T cell counts of 200–349 and >350 cells/mm3 cannot be precisely compared because of the low level of disease progression among these patients during the follow-up period. In addition, groups might differ in key known and unknown prognostic factors that bias the comparison.

In addition to the risks for disease progression, the decision to initiate antiretroviral therapy also is influenced by an assessment of other potential risks and benefits associated with treatment. Potential benefits and risks of early or delayed therapy initiation for the asymptomatic patient should be considered by the clinician and patient [Table 5]. Potential benefits of early therapy include 1) earlier suppression of viral replication; 2) preservation of immune function; 3) prolongation of disease-free survival; and 4) decrease in the risk for viral transmission. Risks include 1) the adverse effects of the drugs on quality of life; 2) the inconvenience of the majority of the available suppressive regimens, leading to reduced adherence; 3) development of drug resistance because of suboptimal suppression of viral replication; 4) limitation of future treatment options as a result of premature cycling of the patient through the available drugs; 5) the risk for transmission of virus resistant to antiretroviral drugs; 6) serious toxicities associated with certain antiretroviral drugs [e.g., elevations in serum levels of cholesterol and triglycerides, alterations in the distribution of body fat, or insulin resistance and diabetes mellitus]; and 7) the unknown durability of effect of available therapies. Potential benefits of delayed therapy include 1) minimization of treatment-related negative effects on quality of life and drug-related toxicities; 2) preservation of treatment options; and 3) delay in the development of drug resistance. Potential risks of delayed therapy include 1) the possibility that damage to the immune system, which might otherwise be salvaged by earlier therapy, is irreversible; 2) the possibility that suppression of viral replication might be more difficult at a later stage of disease; and 3) the increased risk for HIV transmission to others during a longer untreated period. Finally, for certain persons, ascertaining the precise time at which the CD4+ T cell count will decrease to a level where the risk for disease is high might be difficult, and time might be required to identify an effective, tolerable regimen. This task might be better accomplished before reaching a CD4+ T cell count of 200 cells/mm3.

After considering available data in terms of the relative risk for progression to AIDS at certain CD4+ T cell counts and viral loads and the potential risks and benefits associated with initiating therapy, certain specialists in this area believe that the evidence supports initiating therapy for asymptomatic HIV-infected persons with a CD4+ T cell count of <350 cells/mm3 or a viral load of >55,000 copies/mL (by RT-PCR or b-deoxyribonucleic acid [bDNA] assays). For asymptomatic patients with CD4+ T cell counts >350 cells/mm3, rationale exists for both conservative and aggressive approaches to therapy. The conservative approach is based on the recognition that robust immune reconstitution still occurs in the majority of patients who initiate therapy with CD4+ T cell counts in the 200–350 cells/mm3 range, and that toxicities and adherence challenges might outweigh benefits of initiating therapy at CD4+ T cell counts >350 cells/mm3. In the conservative approach, increased levels of plasma HIV RNA (i.e., >55,000 by RT-PCR or bDNA assays) are an indication that more frequent monitoring of CD4+ T cell counts and plasma HIV RNA levels is needed, but not necessarily for initiation of therapy. In the aggressive approach, asymptomatic patients with CD4+ T cell counts >350 cells/mm3 and levels of plasma HIV RNA >55,000 copies/mL would be treated because of the risk for immunologic deterioration and disease progression. The aggressive approach is supported by the observation in multiple studies that suppression of plasma HIV RNA by antiretroviral therapy is easier to achieve and maintain at higher CD4+ T cell counts and lower levels of plasma viral load (6, 3336). However, long-term clinical outcome data are not available to fully endorse this approach.

Data are conflicting regarding sex-specific differences in viral load and CD4+ T cell counts. Certain studies (3743), although not others (4447), have concluded that after adjustment for CD4+ T cell count, levels of HIV RNA are lower in women than men. In those studies that have indicated a possible sex difference in HIV RNA levels, women have had RNA levels that ranged from 0.13 to 0.28 log10 lower than observed among men. In two studies of HIV seroconverters, HIV RNA copy numbers were substantially lower in women than men at seroconversion, but these differences decreased with time; and median viral load in women and men became similar within 5–6 years after seroconversion (3839, 43). Other data indicate that CD4+ T cell counts might be higher in women than men (48). However, importantly, rates of disease progression do not differ in a sex-dependent manner (41, 43, 4950). Taken together, these data demonstrate that sex-based differences in viral load occur predominantly during a window of time when the CD4+ T cell count is relatively preserved, when treatment is recommended only in the setting of increased levels of plasma HIV RNA. Clinicians might consider lower plasma HIV RNA thresholds for initiating therapy in women with CD4+ T cell counts >350 cells/mm3, although insufficient data exist to determine an appropriate threshold. In patients with CD4+ T cell counts <350 cells/mm3, limited sex-based differences in viral load have been observed; therefore, no changes in treatment guidelines for women are recommended for this group.

In summary, the decision to begin therapy for the asymptomatic patient with >200 CD4+ T cells/mm3 is complex and must be made in the setting of careful patient counseling and education. Factors that must be considered in this decision are 1) the willingness, ability, and readiness of the person to begin therapy; 2) the degree of existing immunodeficiency as determined by the CD4+ T cell count; 3) the risk for disease progression as determined by the CD4+ T cell count and level of plasma HIV RNA (1) [Figure; Tables 5 and 6]; 4) the potential benefits and risks of initiating therapy for asymptomatic persons, including short- and long-term adverse drug effects [Table 4]; and 5) the likelihood, after counseling and education, of adherence to the prescribed treatment regimen. Regarding adherence, no patient should automatically be excluded from consideration for antiretroviral therapy simply because he or she exhibits a behavior or other characteristic judged by the clinician to lend itself to nonadherence. Rather, the likelihood of patient adherence to a long-term, complex drug regimen should be discussed and determined by the patient and clinician before therapy is initiated. To achieve the level of adherence necessary for effective therapy, providers are encouraged to use strategies for assessing and assisting adherence: intensive patient education and support regarding the critical need for adherence should be provided; specific goals of therapy should be established and mutually agreed upon; and a long-term treatment plan should be developed with the patient. Intensive follow-up should occur to assess adherence to treatment and to continue patient counseling for the prevention of sexual and drug-injection–related transmission (see Adherence to Potent Antiretroviral Therapy).

Table Jump PlaceholderTable 6.  Indications for Initiating Antiretroviral Therapy for the Chronically Human Immunodeficiency Virus (HIV)-1–Infected Patient

As recommendations evolve, patients who had begun active antiretroviral therapy at CD4+ T cell counts of >350/mm3 might consider discontinuing treatment. Limited clinical data exist addressing whether this should be done or if it can be accomplished safely. Potential benefits include reduction of toxicity and drug interactions, decreased risk for drug-selecting resistant variants, and improvement in quality of life. Risks include rebound in viral replication and renewed immunologic deterioration. If the patient and clinician agree to discontinue therapy, the patient should be closely monitored.