J Am Board Fam Pract: first published as 10.3122/jabfm.6.1.75 on 1 January 1993. Downloaded from Current Report - HIV Antiretroviral Strategies Ronald H. Goldschmidt, MD, Jill]. Legg, MD, and Kirsten A. Brossier, PharmD

Antiretroviral therapy against the human immu­ HN infection CD4+ cell counts decline by nodeficiency virus (HIV) can delay the progres­ about 50 - 85/J.LL per year. Early clinical mani­ sion of HN disease. 1-3 Although it is agreed that festations of HN disease, such as oral candidi­ all patients should be offered antiretroviral ther­ asis and hairy leukoplakia, usually precede the apy, considerable disagreement remains about development of acquired immunodeficiency syn­ the optimal time to initiate treatment and the drome (AIDS). AIDS-defining conditions gen­ choice of drug(s). Because of the paucity of erally occur after CD4+ lymphocyte counts de­ head-to-head studies using clinical endpoints (as cline to fewer than 200/J.LL. AIDS-related opposed to laboratory surrogate markers), no mortality is usually associated with CD4+ cell single treatment regimen can be recommended counts fewer than 50/J.LL. as superior. Furthermore, it has yet to be estab­ lished that antiretroviral therapy prolongs life Reverse Transcriptase Inhibitors for patients with asymptomatic disease.4 Information about antiretroviral treatment Although the absence of a single treatment of comes from clinical drug trials and epidemi­ choice presents difficulties for both the patient ologic studies. Antiretroviral therapy is effective and the physician, the opportunity to offer dif­ in delaying and decreasing clinical endpoints ferent regimens is helpful in the primary care of (i.e., opportunistic infections and malignancies) HN disease. The choice of therapy remains and improving laboratory surrogate markers more a matter of strategy than of science. In this (i.e., CD4+ lymphocyte counts, p24 antigene­ CU'lTent Report - HIV we discuss some of the data mia). Studies that compare surrogate markers as now available on the nucleoside analogs and measures of efficacy are difficult to interpret be­ strategies for antiretroviral therapy. cause modest increases in CD4+ cell counts for short periods of time do not necessarily indicate clinical benefit. Some epidemiologic studies sug­ HIV Disease Pro~ion http://www.jabfm.org/ The natural course of HN disease results in a gest, but do not establish, survival benefit of progressive decline of CD4+ (T-helper) lym­ antiretroviral therapy.5-7 phocyte counts and the development of op­ Three nucleoside analogs, zidovudine, didan­ portunistic infections, malignancies, and other osine, and zalcitabine, have been approved by HN-related illnesses. The normal reference the Food and Drug Administration (FDA). All range of CD4+ lymphocytes is broad and vari­ act by inhibiting reverse transcriptase, an en­ able. CD4+ cell counts are usually near zyme essential to HN replication. on 26 September 2021 by guest. Protected copyright. lOOO/J.LL, but for some persons and some labo­ Zidovudine (AZr, Retrovir), the first agent ratories normal can be fewer than 500/J.LL. With approved, is the antiretroviral drug against which others are measured. Zidovudine delays the development of opportunistic infections and Submitted revised, 19 October 1992. other manifestations of AIDS and might de­ From the Family Practice Residency Program, San Francisco General Hospital and the Department of Family and Community crease mortality in persons with AIDS.I-4 In Medicine (RHG,DL, KAB), and the School of Pharmacy, Division addition, zidovudine has promoted weight gain of Clinical Pharmacy (KAB), University of California, San Fran­ and improved neuropsychiatric function in some cisco. Address reprint requests to Ronald H. Goldschmidt, MD, Director, Family Practice Inpatient Service, San Francisco Gen­ patients. The duration of zidovudine's clinical eral Hospital San Francisco, CA 94110. effectiveness is uncertain. Supported in part by the Western AIDS Education and Train­ Didanosine (ddI, Videx) treatment results in . Center Grant No. I-D35 PE 00108-01, with the Bureau of mg , d S . Adminis· modest improvements in laboratory surrogate Health Professions, Health Resources an .eIV1ces tra- tion, Department of Health and Human SelVlces. markers that are roughly equivalent to those

Current Repon - HIV 75 J Am Board Fam Pract: first published as 10.3122/jabfm.6.1.75 on 1 January 1993. Downloaded from

seen with zidovudine therapy.8-IO In one study becomes a patient receiving lifelong treatment for of patients with a median CD4+ count of 98 a chronic disease. Many patients are under­ cells /j.LL, changing to didanosine after approxi­ standably reluctant to make this change. Never­ mately 1 year of zidovudine therapy resulted in theless, antiretroviral therapy is recommended fewer AIDS-defining events. 11 This advantage to delay progression to AIDS, a key goal of HIV was observed only in patients who did not al­ primary care. ready have AIDS; no survival benefit was evident in any group studied. ProvIder lind Plltient VllrlIIbleS Zalcitabine (ddC, HMD) administration also In clinical medicine the absence of scientific results in modest improvement in surrogate conclusions leads to strong opinions. With a se­ markers of disease progression. I2 Monotherapy rious problem, such as HIV disease, opinions are with zalcitabine does not appear to be as effec­ especially strong - from both the provider and tive as zidovudine for initial therapy. patient-family perspective. Joint decision making The emergence of viral resistance to reverse requires consideration of some key variables. For transcriptase inhibitors is of concern. Data from the physician these variables include interpreta­ in vitro studies suggest that zidovudine resis­ tion of the medical literature, recommendations tance occurs in the first year of treatment. The by consensus panels,13 the influence of local and clinical importance of this observation, however, regional experts, the influence of pharmaceutical is uncertain because the pathogenicity of resis­ company representatives, community standards, tant viruses is poorly understood. Zidovudine­ and the physician's philosophical approach. This resistant viral isolates appear to retain sensitivity last variable deserves more comment. Some phy­ to both didanosine and zalcitabine. Whether al­ sicians prefer to begin treatment as early as pos­ ternating or combining drugs will decrease sible. They might believe that it is wrong to the development of resistance remains to be withhold potentially helpful therapies or that established. early antiretroviral treatment is most effective Combination therapy with zidovudine plus di­ when the viral load is small. Being able to in­ danosine or zalcitabine is under investigation. tervene can be important to the physician­ No clinical endpoint data are available. Zalci­ patient relationship. Other physicians prefer tabine has been given conditional approval for delaying antiretroviral therapy to save drugs use in combination with zidovudine for patients whose effectiveness appears time-limited and to http://www.jabfm.org/ with fewer than 300 CD4+ cells /j.LL based on avoid unnecessary drug toxicities. short-term studies showing improvement in Patients and families also balance many vari­ laboratory surrogate markers. Studies of sequen­ ables. Some want an aggressive pharmacological tial regimens (alternating one agent with an­ attack on HIV using any potentially helpful other for periods of days, weeks, or months) are medication. Others choose to delay or avoid in progress. Sequential therapy has the theoreti­ treatment, perceiving it as more of a burden cal advantage of reducing both toxicity and the than a benefit. Some patients avoid antiretroviral on 26 September 2021 by guest. Protected copyright. emergence of drug resistance. All the nucleoside therapy because it forces them to confront HIV analogs, however, have the same basic mecha­ disease on a daily basis, or they have known part­ nism of action, so their usefulness in combina­ ners, friends, or family members who have done tion might be limited. poorly while receiving antiretroviral therapy. A fourth nucleoside analog, stavudine (d4T), Others want to maximize their health through has improved laboratory surrogate markers in "natural" means. Physicians must recognize that Phase I studies. Although not yet FDA-approved, medical care is only one of many things patients stavudine is available from the manufacturer must consider. Antiretroviral therapy is often less through a Parallel Track (research) protocol. important than such survival issues as food and lodg­ ing, substance use, and family and social problems. strategies of Antiretroviral Th~y The initiation of antiretroviral therapy marks a bnge ofApjn'ollebes milestone in the life of an HIV-infected person. The physician should. choose an antiretrovi­ At this time a person living with HIV infection ral strategy that is consistent with acceptable

76 JABFP Jan.-Feb.I993 Vol. 6 No.1 J Am Board Fam Pract: first published as 10.3122/jabfm.6.1.75 on 1 January 1993. Downloaded from medical practice and the patient's wishes. ~ A broad range of options is available. At Because studies have not established the optimal one extreme, multiple antiretroviral and nonap­ time to initiate or change therapies, the appro­ proved drugs are used as soon as HIV seropo­ priate strategy is one that is most consistent with sitivity is diagnosed, even while CD4+ the patient and physician variables mentioned lymphocyte counts are greater than 500/,.,..L. above. The patient should be allowed flexibility The more common aggressive approach uses in selecting strategies that might be of equiva­ multidrug therapy as soon as CD4+ lymphocyte lent efficacy. A regimen that is unlikely to cause counts are fewer than 500/,.,..L. Available data serious toxicity or interfere with the ability to neither support nor contraindicate such an ap­ administer other essential treatments is pre­ proach. Most physicians in the United States in­ ferred. Table 1 shows toxicity profiles. itiate zidovudine monotherapy when CD4+ We recommend a relatively conservative ap­ lymphocyte counts are consistently fewer than proach. Initiation of antiretroviral therapy can 500/,.,..L. Alternative regimens to zidovudine be offered when the CD4+ count falls to fewer monotherapy are used when recurrent ill­ than 500 cellsl,.,..L on at least two separate oc­ nesses or toxicity occur. At the other extreme, casions. For those who choose not to begin ther­ antiretroviral therapy is avoided altogether apy at this threshold, antiretroviral treatment because of the belief that evidence of effi­ should be encouraged when CD4+ counts are cacy is not strong enough to warrant potential fewer than 400 cells/,.,..L. Because AIDS-defining toxicity. diseases usually occur at CD4+ lymphocyte

Table 1. Approved Antiretroviral Medications.

Drug Common Adverse Effects Drug Interactions Comments Zidovudine (AZT, Malaise, headache, myalgias, Careful monitoring required Can decrease dosage to 100 mg tid for Retrovir) 100 insomnia (often diminish after when used with other nausea, anemia, or neutropenia. mg po 5 times a 4 - 6 weeks of continuous myelosuppressive drugs 60% of plasma drug concentration day or 200 mg use); anemia, granulocyto­ (trimethoprim-sulfameth­ crosses to cerebral spinal fluid (CSF) oxawle, ganiclovir, dapsone, po tid penia, thrombocytopenia; toxic myopathy with long­ and pyrimethamine). Acetaminophen (Tylenol)

term use; blue to black http://www.jabfm.org/ discoloration of nails and skin does not increase zidovudine in pigmented races toxicity. Probenecid increases serum levels of zidovudine

Needs to be administered 2 hours Didanosine (delI, Pancreatitis; dosage-related Two tablets must be taken with each Videx) tablets painfpl peripheral neurop­ before or after administration dose to provide enough buffer for ofdapsone,ketoconazcde,and 2oomgpo bid athy; rash; nausea, abdominal absorption. Tablets must be chewed quinolone antibiotics because for patients >60 cramps, diarrhea; hyper­ thoroughly or crushed. Take only of decreased absorption of on 26 September 2021 by guest. Protected copyright. kg, 125 mgpo glycemia, hyperuricemia; with apple juice or water. Dosages of these drugs caused by the bid for patients hepatitis; headache, insomnia, 300 mg bid are used for patients buffer in didanosine. Careful weighing more than 75 kg. 20% of <60 kg seizures; elevated triglyceride and amylase levels monitoring required when plasma concentration crosses to CSF used with drugs that can cause peripheral neuropathy (isoniazid, metronidawle, vincristine). Do not use concomitantly with intravenous pentamidine because of increased risk of pancreatitis

Careful monitoring required Can decrease dosage to 0.375 mg Zalcitabine (ddC, Painful peripheral neuropathy; when used with other drugs tid for intolerance or for cachec­ HIVID) 0.75 mg pancreatitis; oral and esopha­ geal ulcers; rash; nausea; that can cause peripheral tic patients. 15 % of plasma po tid hepatitis; seizures neuropathy (isoniazid, concentration crosses to CSF metronidawle, vincristine)

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counts fewer than 2001 J.LL, all patients should of the progressive natural history of HIV dis­ receive antiretroviral therapy in advance of this ease, clinical complications will continue to oc­ threshold. cur. When severe immunodeficiency develops Single-agent treatment with zidovudine at (e.g., CD4+ cell counts fewer than 50/J.LL), 500 - 600 mgld is recommended as initial ther­ multiple simultaneous complications are the apy. Zidovudine has been studied more and its rule. At this stage careful medical management clinical efficacy is better established than other of opportunistic infections and other complica­ antiretroviral drugs. Patients who cannot toler­ tions with complex drug regimens can be crucial. ate zidovudine or prefer an alternative drug are The antiretroviral agent least likely to cause offered didanosine. Combination therapy (zi­ drug interactions with other necessary drugs is dovudine and didanosine or zidovudine and zal­ the most appropriate choice. At times, drug in­ citabine) can be substituted for monotherapy if teractions and drug toxicity prohibit antiretrovi­ desired, but it does not have a clear advantage ral therapy. and is more expensive, complicated, and poten­ tially more toxic than monotherapy. Combina­ Conclusion tion therapy with didanosine and zalcitabine is Until well-controlled long-term studies are not recommended because the toxicity profiles completed, the information now available per­ of the two drugs are similar. mits wide latitude in selecting antiretroviral Deciding when a regimen is no longer effec­ strategies. Because patients and their medical tive can be very difficult. Guidelines defining providers have a broad range of approaches to antiretroviral treatment failure have not been HIV disease, treatment should be individualized. established. Indications that a regimen is no When to initiate or change therapy and which longer effective include the development of new agents to use are collaborative decisions to be or recurrent opportunistic infections or malig­ made by the physician and patient. Antiretroviral nancies; disabling clinical symptoms such as drug toxicity should not interfere with the ability weight loss, diarrhea, or unexplained fevers; or to treat opportunistic infections, nor should it a sustained decline in the absolute number and severely decrease the patient's quality of life. At percentage of CD4+ lymphocytes by 50 percent the same time, no patient should progress to se­ or more. Increasingly frequent and severe clini­ vere life-threatening opportunistic infections,

cal problems, occurring despite prolonged treat­ malignancies, or other advanced diseases without http://www.jabfm.org/ ment with an antiretroviral regimen favor having been offered antiretroviral therapy. changing to an alternate agent or combination therapy. Selecting a different antiretroviral regi­ men that causes toxicity or drug interactions, References however, can be more harmful than continuing 1. Volberding P A, Lagakos SW, Koch MA, Pettinelli the same drug. C, Myers MW, Booth DK, et al. Zidovudine in asymptomatic human immunodeficiency virus in­ on 26 September 2021 by guest. Protected copyright. fection. A controlled trial in persons with fewer AIIIlUImuIl ~ than 500 CD4-positive cells per cubic millimeter. Drug therapy for HIV disease is expensive. Be­ The AIDS Clinical Trials Group of the National fore offering treatment options, it is important Institute of Allergy and Infectious Diseases. N Engl to assess the reimbursement mechanisms avail­ J Med 1990; 322:941-9. able through the patient's insurance or state 2. Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, et al. The efficacy funding mechanisms. It is counterproductive to of azidothymidine (AZ1) in the treatment of pa­ decide upon one of many equivalent regimens if tients with AIDS and AIDS-related complex. A the cost is prohibitive. double-blind, placebo-controlled trial. N Engl J Prophylaxis against Pneumocystis carin;; pneu­ Med 1987; 317:185-91. monia (PCP) when indicated (for patients with 3. Fischl MA, Parker CB, Pettinelli C, Wulfsohn M, fewer than 200 CD4+ cells! J.LL, past episodes Hirsch MS, Collier AC, et al. A randomized con­ trolled trial of a reduced daily dose of zidovudine in of PCP, or advanced symptomatic disease) and patients with the acquired immunodeficiency syn­ careful management of opportunistic infections drome. The AIDS Clinical Trials Group. N Engl J are essential components of HIV care. Because Med 1990; 323:1009-14.

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4. Hamilton JD, Hartigan PM, Simberkoff MS, 9. Drusano GL, Yuen GJ, Lambert JS, Seidlin M, Day PL, Diamond GR, Dickinson GM, et aI. A con­ Dolin R, Valentine IT. Relationship between dide­ trolled trial of early versus late treattnent with zi­ oxyinosine exposure, CD4 counts, and p24 anti­ dovudine in symptomatic human immunodeficiency gen levels in human immunodeficiency virus virus infection. Results of the Veterans Affairs Coop­ infection. A Phase I trial. Ann Intern Med 1992; erative Study. N EnglJ Med 1992; 326:437-43. 116:562-6. 5. Graham NM, Zeger SL, Park LP, Vermund SH, 10. Cooley TP, Kunches LM, Saunders CA, Ritter JI(, Detels R, Rinaldo CR, et al. The effects of survival Perkins CJ, McLaren C, et al. Once-dailyadmini­ of early treattnent of human immunodeficiency vi­ stration of 2',3' -dideoxyinosine (ddl) in patients rus infection. N EnglJ Med 1992; 326:1037-42. with the acquired immunodeficiency syndrome or 6. Graham NM, Zeger SL, Park LP, Phair JP, Detels AIDS-related complex. Results of a Phase I trial. R, Vermund SH, et al. Effect of zidovudine and N EnglJ Med 1990; 322:1340-5. Pneumocystis carm;; pneumonia prophylaxis on 11. Kahn JO, Lagakos SW, Richman DD, Cross A, progression of HIV-l infection to AIDS. The Pettinelli C, Liou SH, et al. A controlled trial com­ Multicenter AIDS Cohort Study. Lancet 1991; paring continued zidovudine with didanosine in 338:265-9. human immunodeficiency virus infection. The 7. Moore RD, HidalgoJ, Sugland BW, Chaisson RE. NIAID AIDS Clinical Trials Group. N EnglJ Med Zidovudine and the natural history of the acquired 1992; 327:581-7. immunodeficiency syndrome. N Engl J Med 1991; 12. Meng TC, Fischl MA, Boota AM, Spector SA, 324:1412-6. Bennett D, Bassiakos Y, et al. Combination therapy 8. Lambert JS, Seidlin M, Reichman RC, Plank CS, with zidovudine and dideoxycytidine in patients with Laverty M, Morse GD, et al. 2',3'-dideoxyinosine advanced human immunodeficiency virus infection. (ddl) in patients with the acquired immunodefi­ A Phase IIII study. Ann IntemMed 1992; 116:13-20. ciency syndrome or AIDS-related complex. A 13. Recommendations for zidovudine: early infection. Phase I trial. N EnglJ Med 1990; 322:1333-40. JAMA 1990; 263:1606,1609. http://www.jabfm.org/ on 26 September 2021 by guest. Protected copyright.

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