Portal de Periódicos da CAPES

Update on HAART in HIV

2005; Elsevier BV; Volume: 44; Linguagem: Inglês

10.1016/j.jhep.2005.11.021

1600-0641

Patrick Yéni,

HIV/AIDS Research and Interventions

Highly active antiretroviral combination therapy (HAART) has been responsible for a dramatic decrease in AIDS mortality since 1996, and has changed the clinical profile of HIV infection from a sub-acute lethal to a chronic ambulatory disease. HAART consists of a double nucleoside (NRTI) backbone plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir pharmacologically enhanced protease inhibitor (PI/r). Triple NRTI combinations are less potent than 2NRTIs/NNRTI or 2NRTIs/PI/r combinations. Antiretroviral first-line therapy is rapidly moving towards more convenient and less toxic regimens. Three double NRTI co-formulations are now available, and the risk of mitochondrial toxicity is low with drugs such as 3TC, FTC and tenofovir. Similarly, atazanavir, a recently available PI, can be given once daily and is less metabolically toxic than other PIs. Antiretroviral salvage therapy takes advantage of the development or availability of new drugs, either from existing (tipranavir, TMC 114 as new PIs) or new classes (T20 as a fusion inhibitor), that remain active on many triple-class drug resistant viruses. More progress is needed in the field of drug discovery, since a significant proportion of patients still die from AIDS with a multi-resistant virus, and since the incidence of primary HIV resistance is increasing in various parts of the world. Highly active antiretroviral combination therapy (HAART) has been responsible for a dramatic decrease in AIDS mortality since 1996, and has changed the clinical profile of HIV infection from a sub-acute lethal to a chronic ambulatory disease. HAART consists of a double nucleoside (NRTI) backbone plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir pharmacologically enhanced protease inhibitor (PI/r). Triple NRTI combinations are less potent than 2NRTIs/NNRTI or 2NRTIs/PI/r combinations. Antiretroviral first-line therapy is rapidly moving towards more convenient and less toxic regimens. Three double NRTI co-formulations are now available, and the risk of mitochondrial toxicity is low with drugs such as 3TC, FTC and tenofovir. Similarly, atazanavir, a recently available PI, can be given once daily and is less metabolically toxic than other PIs. Antiretroviral salvage therapy takes advantage of the development or availability of new drugs, either from existing (tipranavir, TMC 114 as new PIs) or new classes (T20 as a fusion inhibitor), that remain active on many triple-class drug resistant viruses. More progress is needed in the field of drug discovery, since a significant proportion of patients still die from AIDS with a multi-resistant virus, and since the incidence of primary HIV resistance is increasing in various parts of the world. Starting in 1996, the mortality rate of HIV-infected patients has dramatically decreased in western countries, when highly active antiretroviral combination therapy (HAART) became available [[1]Palella F.J. Delaney K.M. Moorman A.C. Loveless M.O. Fuhrer J. Satten G.A. et al.Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.N Engl J Med. 1998; 338: 853-860Crossref PubMed Scopus (8616) Google Scholar]. For example, the average mortality rate was over 50,000 cases in 1995, compared to less than 20,000 cases in 2002 in the USA. Approximately, 40% of deaths in HIV-infected patients are HIV-related, the next leading causes being liver-related, treatment complications, and suicide/drug overdose [[2]Konopnicki D. Mocroft A. De Wit S. Antunes F. Ledergerber B. Katlama C. et al.Hepatitis B and HIV: prevalence, AIDS progression, response to HAART and increased mortality in the Euro SIDA Cohort.AIDS. 2005; 19: 593-601Crossref PubMed Scopus (441) Google Scholar]. HAART has changed the clinical profile of HIV infection from a subacute lethal disease to a chronic ambulatory disease. Because current therapy cannot eradicate HIV-infection, the goal of antiretroviral therapy is to achieve and maintain an HIV-RNA copy number in the plasma (viral load) at an undetectable level, using the most sensitive routinely available assays (<50 copies/ml) [[3]Yeni P.G. Hammer S.M. Hirsch M.S. Saag M.S. Schechter M. Carpenter C.C. et al.Treatement for adult HIV infection. 2004 recommendations of the international AIDS society—USA panel.J Am Med Assoc. 2004; 292: 251-265Crossref Scopus (533) Google Scholar]. It has repeatedly been shown that an undetectable viral load in the plasma is associated with the largest increase in CD4+ blood cell counts towards normal values, the most prolonged effect on the control of virus replication, and the lowest level of virus evolution with time (in particular for resistance to antiretroviral drugs). When an effective therapy is withdrawn, a rapid increase in plasma HIV-RNA level and decrease in CD4+ blood cell counts to pre-therapy values is observed. Therefore, the duration of antiretroviral therapy is lifelong with the drugs currently available. The increase in the duration of time spent under antiretroviral therapy has led to the identification of severe and delayed, drug-class specific, adverse events [[4]Schambelan M. Benson C.A. Carr A. Currier J.S. Dube M.P. Gerber J.G. et al.Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an international AIDS society—USA panel.J Acquir Immune Defic Syndr. 2002; 31: 257-275Crossref PubMed Scopus (341) Google Scholar]. Most complications associated with NRTI therapy are the consequence of the capacity of these drugs to inhibit host mitochondrial DNA polymerase. The adverse effects of most concern involving NRTIs are lactic acidosis, subcutaneous lipoatrophy, peripheral neuropathy and pancreatitis. There is a wide range of severity of these adverse reactions, but lactic acidosis (often associated with hepatic steatosis) and pancreatitis may be life-threatening. It should be noted that the risk of mitochondrial toxicity is different among drugs in this class, higher with d4T and ddI than with ZDV, and low with 3TC, FTC and TDF. The risks associated with the use of NNRTIs are essentially skin reactions (that may be life-threatening with NVP) and toxic hepatitis, occurring usually early during therapy. The major complications of PI therapy are progressive accumulation of visceral fat and metabolic disorders such as insulin resistance (rarely, overt diabetes) and hyperlipidemia. An association between duration of HAART and the incidence of myocardial infarction has been demonstrated. Current guidelines [[3]Yeni P.G. Hammer S.M. Hirsch M.S. Saag M.S. Schechter M. Carpenter C.C. et al.Treatement for adult HIV infection. 2004 recommendations of the international AIDS society—USA panel.J Am Med Assoc. 2004; 292: 251-265Crossref Scopus (533) Google Scholar] for the treatment of HIV infection have incorporated recent data on activity and toxicity of antiretroviral agents, including recently released drugs, as well as the effects of various treatment strategies, in order to answer the following key questions: When to start antiretroviral therapy, what to start with, when and how to change? It remains undemonstrated whether HIV primary infection should be treated. Most experts would treat severe, symptomatic, primary infections, in particular when neurologic symptoms are present or CD4+ cell counts are low. The appropriate duration of therapy is unknown. Chronically infected patients presenting with minor HIV-related symptoms should be treated, because the risk of rapid progression to overt HIV disease is high. In asymptomatic chronically infected patients, the decision of when to start therapy is essentially based on CD4+ cell counts, but there is no strictly defined CD4 count under which treatment should be initiated in all patients [[3]Yeni P.G. Hammer S.M. Hirsch M.S. Saag M.S. Schechter M. Carpenter C.C. et al.Treatement for adult HIV infection. 2004 recommendations of the international AIDS society—USA panel.J Am Med Assoc. 2004; 292: 251-265Crossref Scopus (533) Google Scholar]: Given the risk of occurrence of severe opportunistic infections, all patients with a CD4+ count of less than 200 cells/mm3 should be treated; conversely, most patients with a CD4+ count higher than 350 cells/mm3 should be monitored untreated, because the risk of treatment toxicity outweighs the risk of clinical progression of HIV infection. In the 200–350 cells/mm3 range, the decision is individualized, based on factors such as the CD4+ count, the slope of CD4+ count decline, the HIV-RNA level in plasma and the willingness of the patient to start a lifelong therapy that requires an excellent compliance despite various inconvenients. The recommendations of when to start therapy are not based on strong evidence for two reasons: Data supporting the recommendations are derived from cohort studies [5Palella F.J. Deloria-Knoll M. Chmiel J.S. Moorman A.C. Wood C.K. Greenberg A.E. et al.Survival benefit of initiating antiretroviral therapy in HIVinfected persons in different CD4+ cell strata.Ann Intern Med. 2003; 138: 620-626Crossref PubMed Scopus (386) Google Scholar, 6Chene G. Sterne J.A. May M. Costagliola D. Ledergerber B. Phillips A.N. et al.Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies.Lancet. 2003; 362: 679-686Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, 7Egger M. May M. Chene G. Phillips A.N. Ledergerber B. Dabis F. et al.Prognosis of HIV-1 infected drug naive patients starting potent antiretroviral therapy: a collaborative analysis of prospective studies.Lancet. 2002; 360: 119-129Abstract Full Text Full Text PDF PubMed Scopus (1336) Google Scholar, 8Sterling T.R. Chaisson R.E. Keruly J. Moore R.D. Improved outcomes with earlier initiation of highly active antiretroviral therapy among human immunodeficiency virus-infected patients who achieve durable virologic suppression: longer follow-up of an observational cohort study.J Infect Dis. 2003; 188: 1659-1665Crossref PubMed Scopus (78) Google Scholar], not randomized clinical trials and, therefore, are subjected to various biases. In addition, the recommendations are based on an evaluation of the risk and the benefit of therapy with available drugs. Would the risk/benefit ratio be different with future drugs, the decision of when to start therapy might be taken for higher CD4+ counts than recommended today. They act on three different virus targets:1.The reverse transcriptase. Two drug classes are active on this virus enzyme: The nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs).2.The protease. the bioavailability of many protease inhibitors (PIs) is increased when given with small (virologically ineffective) doses of ritonavir (r), resulting in increased potency and more convenient dosing.3.A region of the gp 41 involved in the fusion of the virus envelope with the target cell membrane. T20 (or enfuvirtide) is the only drug in this class, administered bid subcutaneously. Highly active antiretroviral therapy is expected to result in undetectable plasma viral load in most patients. To achieve this goal, 2 NRTIs are combined with either a NNRTI or a PI/r. NNRTIs are more often used than PIs in this setting, because they are more convenient to dose. In addition, no PI was shown to be superior to efavirenz (EFV, one of the two available drugs in the class), whereas EFV gave results superior to several PIs, in terms of percentage of patients with undetectable viral load after 1 year or more of therapy. EFV is less toxic than nevirapine (NVP, the other NNRTI available), in particular for the skin and the liver, and particularly in certain populations of patients such as women with CD4+ counts higher than 250/mm3. However, the occurrence of teratogenicity with EFV is demonstrated in humans. It is now considered that PIs should be used combined to small doses (100 mg once or twice daily), of r ('boosted' PIs, PI/r see above). There is no data to select one PI over another, based on antiviral potency. The largest amount of data has been produced with lopinavir/r (LPV/r) [[9]Walmsley S. Bernstein B. King M. Arribas J. Beall G. Ruane P. et al.Lopinavir ritonavir versus nelfinavir for the initial treatment of HIV infection.N Engl J Med. 2002; 346: 2039-2046Crossref PubMed Scopus (637) Google Scholar]. Atazanavir (ATV) [[10]Squires KE, Thiry A, Giordano M, for the AI424-034 International Study Team. Atazanavir (ATV) QD and efavirenz (EFV) QD with fixed-dose ZDV+3TC: comparison of antiviral efficacy and safety through wk 24. In: Forty-second interscience conference on antimicrobial agents and chemotherapy, September 27–30, San Diego, CA; 2002 [Abstract AI424-034].Google Scholar] has been recently available and is the only PI given once a day. In addition, it might exert a less toxic effect on plasma lipids than other PIs. It has become clear that the combination of 2 NRTIs with a third NRTI is less active than the combination of 2 NRTIs with either a NNRTI [[11]Gulick R.M. Ribaudo H.J. Shikuma C.M. Lustgarten S. Squires K.E. Meyer III, W.A. et al.Triple nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection.N Engl J Med. 2004; 350: 1850-1861Crossref PubMed Scopus (487) Google Scholar] or a PI/r. Therefore, such a combination is not recommended anymore. If necessary under special circumstances (toxicity, compliance), its use should be restricted to ZDV/3TC/ABC (Trizivir), given the available data. Several NRTI dual combinations can be used as 'backbones' of HAART. The d4T/ddI combination is not recommended for toxicity reasons [[12]Robbins G.K. De Gruttola V. Shafer R.W. Smeaton L.M. Snyder S.W. Pettinelli C. et al.Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection.N Engl J Med. 2003; 349: 2293-2303Crossref PubMed Scopus (328) Google Scholar]. The ZDV/3TC combination is frequently used for reasons of convenience (drug coformulation, 1 od pill) and acceptable toxicity. In addition to ZDV/3TC, two combinations are coformulated, lowering the pill burden: 3TC/ABC and TDF/FTC. Both are given as one pill od. TDF/FTC has been shown to be more active than ZDV/3TC, probably for toxicity reasons. Such coformulations will probably become the standard of care for first-line therapy: As an example, the TDF/FTC/EFV HAART regimen is given as 2 pills od, and work is in progress to coformulate the three drugs in one pill only. It should be noted that TDF, a nucleotide analogue, does not share the risk of mitochondrial toxicity common to nucleoside analogues. Finally, the 3 coformulations exert a one—or dual—drug activity against HBV. Changes in therapy are frequent during patients' treatment history, and may be caused by many factors: suboptimal compliance, intolerance or overt toxicity, virologic failure, availability of more convenient regimens. This paper will only address salvage therapy in case of treatment failure, although this is not the most frequent reason for changing therapy. Principles, new drugs and strategies will be discussed.(1)Principles [[3]Yeni P.G. Hammer S.M. Hirsch M.S. Saag M.S. Schechter M. Carpenter C.C. et al.Treatement for adult HIV infection. 2004 recommendations of the international AIDS society—USA panel.J Am Med Assoc. 2004; 292: 251-265Crossref Scopus (533) Google Scholar]. Virologic failure is defined as a viral load repeatedly detectable during therapy. Transitory unique episodes of detectable low grade ( 100/mm3), because of the risk of a profound CD4+ decrease during the treatment interruption phase [[16]Lawrence J. Mayers D.L. Huppler Hullsiek K. Collins G. Abrams D.I. Reisler R.B. et al.Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus.N Engl J Med. 2003; 349: 837-846Crossref PubMed Scopus (221) Google Scholar].