Guidelines for the Use of Antiretroviral Agents in Hiv-Infected Adults and Adolescents

GUIDELINES FOR THE USE OF ANTIRETROVIRAL AGENTS IN HIV-INFECTED ADULTS AND ADOLESCENTS [Department of Health and Human Services (http://www.hivatis.org)]: These are the revised guidelines from DHHS, which became official February 4, 2002. This is a “living document” so that many of the changes from the previous official release had already been posted on the HIV/AIDS Treatment Information Service web site. Highlights include the following. Who Should Be Treated? The guidelines for initiating antiretroviral therapy are somewhat more conservative based on the following observations: The infection cannot be cured with present drugs; there has been no convincing benefit to therapy when initiated before a CD4 cell count threshold of 200/mm3; treatment is associated with substantial toxicity and adherence requirements; and, treatment introduces the risk of production of resistant strains. Nevertheless, there are massive data showing the great benefit of therapy for those with more advanced disease in terms of viral suppression, immune recovery, and reduction in mortality and AIDS-associated complications. The major prognostic indicator is the CD4 cell count; viral load also influences prognosis, but is less important than the CD4 cell count. It should be emphasized that patient readiness is a critical component of the decision to initiate antiretroviral therapy. On the basis of these observations, the following recommendations are made (Table 1).TABLE 1: Who should be treated?What To Start With? Recommendations are based on data showing viral suppression in therapeutic trials with treatment-naïve patients in which the data are considered scientifically robust based on sample size, comparator (another regimen in the preferred category), adequate duration (24 weeks, but preferably 48 weeks), virologic end points (< 20–50 c/mL and < 500 c/mL), adequate analysis (intent-to-treat and as-treated analyses), description of adverse events, and accounting for all patients. Additional considerations include quality of life issues such as demands of the regimen (pill burden, food requirements, dosing frequency, etc.) and side effect profile. On the basis of these observations, the following recommendations were made (Table 2).TABLE 2: Recommended Regimens—Initial treatment (one each from column A and B)Laboratory Tests CD4 cell count should usually be monitored at 3–6 month intervals. The 95% confidence interval is 30% for the absolute count and 3% for the percentage. A plasma HIV RNA should be monitored immediately prior to therapy and again weeks after HAART with the expectation of a 1.0 log10 decrease at 2–8 weeks and < 50 c/mL by 16–20 weeks. Monitoring of viral load should take place at 3–4 month intervals. Discordance between the CD4 cell count and plasma HIV RNA is found in up to 20%; in these cases, therapeutic decisions are usually based on viral load results. Previous guidelines distinguished viral load results with RT-PCR and bDNA analyses; for the current bDNA assay (version 3.0), these two assays are considered comparable except at < 1500 c/mL. Resistance testing: This assay is recommended for virologic failure during HAART and when there is suboptimal suppression of viral load after initiation of antiretroviral therapy. Resistance testing should be “considered” in drug selection for acute HIV infection; however, it is not recommended in chronically infected patients before initiation of therapy, after discontinuation of antiretroviral agents, or when the viral load is too low for measurement (usually less than 1,000 c/mL). For information regarding interpretation of resistance mutations, see http://hiv-web.lanl.gov. Primary HIV Infection The preferred diagnostic test is HIV RNA when serology is negative or indeterminate. The decision to treat with antiretroviral agents is based on theoretical considerations; clinical trial data are limited, but supportive of treatment. Pregnancy Indications to treat are based on current guidelines, but also include any pregnant woman with HIV RNA levels exceeding 1,000 c/mL. The recommended antiretroviral regimen is identical to that recommended above for nonpregnant women, but should include the three-part ZDV regimen from the PACTG protocol 076 (ZDV starting at 14 weeks gestation and continue throughout pregnancy, IV therapy during labor, and oral administration to the newborn for the first 6 weeks). Women in the first trimester of pregnancy may wish to delay therapy until after 10–12 weeks gestation because this is the period of organogenesis. In addition, nausea and vomiting in early pregnancy may influence GI tolerance of these drugs and adherence. Nevertheless, many authorities recommend standard treatment regardless of gestational age if there are indications for HAART. Efavirenz should be avoided during the first trimester because of teratogenic effects in rhesus macaques. Hydroxyurea should also be avoided because it is a potent teratogen. The combination of ZDV and d4T should be avoided (pharmacologic antagonism), and the combination of d4T and ddI should be used “only when other nucleoside combinations have failed or caused unacceptable toxicity” (due to increased risk of lactic acidosis). AZT monotherapy may be an appropriate option for untreated women with a viral load < 1,000 c/mL and for some who wish to restrict exposure of their fetus to these drugs but still want to reduce the risk of transmission. Reduction of viral load to < 1000 c/mL “limits the need to consider elective caesarean delivery.” Structured Treatment Interruption There are three major STI strategies including the following: STI for salvage therapy: Not recommended. STI for “autoimmunization” with better immune regulation of HIV: this is currently under study and data are inadequate to recommend it. STI to reduce total time of ART: the number of patients and duration of follow-up are inadequate for a recommendation. Criteria to Change Therapy Virologic criteria: With initial treatment, the failure to decrease plasma HIV RNA 0.5–0.75 log10 at 4 weeks or one log10 by 8 weeks (optional) or failure to suppress HIV to undetectable levels at 4–6 months (recommended, but must also consider baseline viral load). For patients who have achieved complete suppression, low-level detection (50–5,000 c/mL) should be followed closely, and those with a significant increase (three-fold or greater from nadir) are not attributed to intercurrent infection, vaccination, or test methods considered virologic failures. Immunologic: persistent decline in CD4 cell count is an “optional” reason to change therapy. Clinical failure with an AIDS-defining diagnosis: this is not considered grounds for changing therapy unless accompanied by CD4 cell decline and/or virologic failure. Prevention: The following elements are emphasized: Each patient encounter should include an assessment of the patient’s knowledge and understanding of HIV transmission and should include a discussion of methods to prevent transmission. Previous studies have shown a one log reduction in VL reduces the probability of transmission between discordant couples by 2.5 fold. Nevertheless, there are important exceptions to risks based on viral load and probability of transmission. There appears to be a “rough correlation” between plasma HIV levels and genital HIV levels, but there are important exceptions, and viral evolution may occur in the genital compartment distinct from viral evolution in plasma. Biologic factors that influence probability of transmission include viral load, STDs, vaginitis, nonoxynol-9 use, menstruation, oral contraceptives, estrogen deficiency, progesterone access, lack of circumcision, vitamin A deficiency, and selenium deficiency. The provider or a referral service should provide partner notification. To prevent sexual transmission, “there is no substitute for latex or polyurethane male or female condoms” and there should also be other safe sex behaviors including partner reduction and abstinence. For injection drug users, the recommendation is cessation of sharing of drug paraphernalia and participation in drug rehabilitation programs. Class Adverse Reactions The following is a brief and probably over-simplistic summary of new data provided for class adverse reactions (Table 3).TABLE 3: Class Adverse Reactions