Antiretroviral therapy for patients with HIV disease

Our approach to the treatment of patients infected with the human immunodeficiency virus (HIV) has changed significantly over the past 2 years. This follows a number of recent advances which include a better understanding of HIV pathogenesis, the development of new techniques for sensitive and accurate quantification of HIV-1 RNA in plasma, availability of newer antiretroviral agents and the demonstration that combination therapy is more effective than monotherapy [1–6]. Consequently, there are now fewer HIV related deaths and opportunistic infections in addition to a reduction in hospital admissions and lengths of stay [7–8]. We review these recent advances and how they influence the management of HIV disease in the clinical setting. Infection with HIV-1 initiates progressive destruction of the CD4 T lymphocyte. The rate of CD4 T-cell decline determines the rate of immunodeficiency and the subsequent development of HIV related opportunistic infections and malignancies [9, 10]. This destruction of the T-cell is due mainly to active viral replication which demonstrates considerable interindividual variability. The average time to development of the acquired immunodeficiency syndrome (AIDS) following HIV-1 infection is approximately 10 years. However some individuals (20%) will develop AIDS within 5 years of infection whereas a smaller proportion (5%) will remain asymptomatic for over 10 years without a significant decline in CD4 T cell count. For these patients with slowly progressive HIV disease viral replication is contained and proceeds at extremely low levels [11]. The development of new techniques for sensitive and accurate quantification of HIV-1 RNA in plasma has enhanced our knowledge and understanding of HIV replication and the pathogenesis of AIDS. Using methodology such as target amplification (e.g. quantitative reverse transcriptase polymerase chain amplification, Amplicor Roche Molecular Systems) enables the determination of HIV-1 RNA levels as low as 20 copies ml−1. Whilst the results from the commonly used assays are strongly correlated the absolute values of HIV RNA measured in the same sample can differ by threefold. Therefore measurement of two samples at baseline in clinically stable patients is recommended as a means of reducing the variability of plasma HIV RNA assays. The quantity of HIV-1 RNA in the plasma accurately reflects the extent of virus replication as even moderate levels of HIV RNA are associated with active replication in lymphoreticular tissue [12, 13]. Viral replication in some compartments e.g. central nervous system may not be accurately reflected by plasma HIV RNA. Plasma HIV RNA may show significant variation depending on the stage of infection. In primary HIV-1 infection concentrations of plasma HIV RNA may exceed 107 copies ml−1 [14]. The emergence of an immune response results in a steady state level after approximately 6 months. This level is referred to as the viral load ‘set point’ which will vary between patients but will frequently lie between 103 and 105 copies HIV RNA per ml (Figure 1). This set point may remain stable for many years but eventually the HIV RNA value increases with a deterioration in immune function and the development of opportunistic infections and neoplasms. HIV infection is a dynamic process of CD4 T cell production and destruction mediated by viral replication. It has been estimated that 108 virus particles are produced each day to maintain steady state. Recent work demonstrates the prognostic value of HIV RNA measurement at steady state (set point) [15, 16]. A clear gradient of disease progression and death with increasing concentrations of plasma HIV RNA has been shown (Table 1). In contrast baseline CD4 T cell counts had no discriminatory value in predicting disease progression except when counts fall below 320×106 l−1. The independence of viral load information from CD4 counts is demonstrated by the findings from patients with CD4 counts greater than 500×106 l−1 where 50% of patients with HIV RNA levels greater than 10 900 copies ml−1 died within 6 years compared with 5% with HIV RNA levels below 10 900 copies ml−1 [15]. Such information is reflected in recent guidelines for initiation of antiretoviral therapy in HIV disease. Plasma HIV RNA and CD4 count during the course of HIV-1 infection. Most clinicians would agree that antiretroviral therapy should be introduced before substantial immunodeficiency ensues. As the onset of HIV related symptoms (e.g. recurrent oral candidiasis, oral hairy leukoplakia, chronic fever, weight loss) is a strong predictor of further progression to HIV related opportunistic infections all patients with symptomatic HIV disease should be treated [17]. The difficulty arises for patients who are asymptomatic, hence the need for a marker that can predict the rate of disease progression. Since the availability of HIV RNA levels there have been a number of guidelines on initiation of anti HIV therapy, the most recent published in June 1997 [18–20]. For asymptomatic patients therapy is recommended if the CD4 cell count falls below 500×106 l−1, this is particularly useful if HIV RNA assays are not available. Treatment with anti HIV drugs is now advised for all patients with plasma HIV RNA concentrations greater than 5000 to 10 000 copies ml−1 regardless of the CD4 cell count (Table 2). The recent trend has certainly been towards the early introduction of antiretroviral therapy. Having decided to treat a patient with anti-HIV drugs the clinician must then decide which drugs to use. The first group of drugs available for the treatment of HIV disease inhibited the HIV reverse transcriptase enzyme. These included the nucleoside analogues zidovudine (ZDV), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC) and stavudine (d4T). The nucleosides are taken up by target cells, phosphorylated to the 5′-triphosphate by cellular enzymes to produce the active drug [21]. Also inhibiting reverse transcriptase are the non nucleosides nevirapine (NVP) and delavirdine (DEL) [22]. The third group of drugs now available for the treatment of HIV disease are the protease inhibitors [23]. The HIV protease enzyme is responsible for the post translational processing of gag and gag-pol polyprotein precursors into their functional products. Inhibition of this enzyme results in the production of non infectious virus [24]. Protease inhibitors currently available are saquinavir (SQV), ritonavir (RIT), indinavir (IND) and nelfinavir (NEL). The site of action of these drugs is shown in Figure 2. Life cycle of HIV-1 demonstrating the sites of action of currently available antiretroviral drugs. The efficacy of zidovudine in the treatment of patients with AIDS and advanced HIV disease was first reported in 1987, however clinical experience with ZDV demonstrated that its beneficial effects were not sustained due in part to the emergence of resistant viral strains [25, 26]. In an attempt to improve clinical outcome combinations of ZDV with other nucleoside analogues were considered, as synergistic anti HIV effects had been demonstrated in vitro [27]. This raised the possibility of a delay in the emergence of resistant viruses with a more sustained antiviral effect. This was supported by surrogate marker changes from a number of short term studies [28, 29]. Therefore a number of large scale randomized trials were undertaken to investigate the potential benefits of combination therapy with nucleoside analogues. These trials began in 1991 (ACTG 175), 1992 (Delta, CPCRA) and 1995 (CAESAR). The preliminary results of these trials were published in 1995 demonstrating the beneficial effects of combination therapy and thus brought an end to the era of monotherapy [30]. The important findings from these trials are discussed below. ACTG 175 was a randomized, double-blind, placebo-controlled trial to compare monotherapy with zidovudine (ZDV) or didanosine (ddI) with combination therapy including ZDV plus ddI or ZDV plus zalcitabine (ddC) in adults infected with HIV-1 [4]. All 2467 patients had CD4 cell counts between 200 and 500×106 l−1 and were randomized to the following regimens ZDV 600 mg daily, ZDV 600 mg+ddI 400 mg daily, ZDV 600 mg+ddC 2.25 mg daily or ddI 400 mg daily. The primary end point for the study was a greater than 50% decline in the CD4 count, development of AIDS, or death. The median follow up was 143 weeks. Progression to the primary end point was more frequent with ZDV monotherapy (32%) when compared with ZDV+ddI (18%), ZDV+ddC (20%) or ddI monotherapy (22%). The incidence of an AIDS defining event or death was 16% for ZDV monotherapy, 11% for ZDV+ddI, 12% with ZDV+ddC and 11% for ddI monotherapy. The difference between ZDV alone and each of the two ddI groups was statistically significant. Similarly the mortality rate was significantly reduced in patients treated with ZDV+ddI (5%), ddI (5%) but not for ZDV+ddC (7%) when compared with ZDV monotherapy (9%). Therefore despite the fact that changes in CD4 cell count constituted 71% of primary end points, regimens containing ddI were superior to ZDV monotherapy in preventing clinical end points. Sub group analysis among patients with no prior antiretroviral therapy demonstrated all treatments were superior to ZDV alone in preventing a primary end point. In preventing AIDS or death, only ZDV+ddC proved superior to ZDV alone whereas no difference in mortality was demonstrated between the four treatment groups reflecting the lower incidence of end points in the antiretroviral naïve group. Subgroup analysis of the 57% of patients with previous antiretroviral therapy demonstrated the superiority of ddI containing regimens in reducing the incidence of clinical end points. The mortality in patients treated with ZDV+ddI was 6%, ddI alone 5%, ZDV+ddC 9% and ZDV monotherapy 10%. The ACTG 175 study suggests that for patients with no prior antiretroviral therapy treatment with ZDV+ddI, ZDV+ddC or ddI monotherapy will be superior to ZDV monotherapy and for patients who have been treated with antiretroviral therapy a change to ZDV+ddI or ddI monotherapy would be beneficial. The study also suggests that treatment of patients with relatively early HIV disease using ZDV+ddI or ddI may produce substantial clinical benefits. With respect to adverse effects there was no significant increase in symptoms reported by patients treated with combination therapy. However laboratory abnormalities were higher as subjects treated with ZDV+ddI had the highest elevation in liver enzymes (9.9%) and ZDV+ddC produced greater haematological abnormalities (anaemia and neutropenia) in 10% of patients. It must be noted that 53% of patients in ACTG 175 discontinued the study treatment prematurely and 19% were lost to follow up, however the investigators argued that this did not negate the differences between treatments. The European Australian Delta study was a randomized, double-blind study comparing ZDV 600 mg daily with ZDV 600 mg+ddI 400 mg daily or ZDV 600 mg+ddC 2.25 mg daily in patients with HIV disease [5]. All 3207 patients had a CD4 count less than 350×106 l−1 or had symptoms of HIV disease. Patients with AIDS had CD4 counts greater than 50×106 l−1. The primary end points were death and AIDS or death in patients without AIDS at entry. The median follow up was 30 months. The Delta study was subdivided into two groups consisting of patients who had not had ZDV prior to study (Delta 1) and for those who had at least 3 months ZDV therapy (Delta 2). For patients without prior ZDV therapy the mortality among patients treated with ZDV alone was 21% compared with 13% for ZDV+ddI and 15% for ZDV+ddC. The reduction in mortality produced by combination therapy was statistically significant. For ZDV experienced patients mortality was 35% for ZDV, 28% for ZDV+ddI and 33% for ZDV+ddC. Only the ZDV+ddI combination resulted in a significant reduction in mortality. For patients ZDV naïve and without an AIDS defining illness at study entry there was a delay in disease progression in the ZDV+ddI treatment group. Patients with an AIDS diagnosis at study entry did benefit from combination therapy with ZDV+ddI and ZDV+ddC reducing progression to advanced AIDS or death by 54% and 44% respectively in Delta 1. In Delta 2 only the ZDV+ddI combination reduced disease progression (by 40%) in patients with AIDS. When compared with the ACTG 175 study, participants in Delta had more advanced disease (45% symptomatic) and less exposure to antiretroviral therapy (66% ZDV naïve). The important finding from the Delta trial was the significant reduction in mortality associated with combination therapy with ZDV+ddI or ZDV+ddC when compared with ZDV monotherapy. The benefit was more pronounced among patients without prior antiretroviral therapy. In patients with previous ZDV exposure the addition of ddI, but not ddC, improved survival. As in the ACTG 175 study many patients in Delta discontinued trial therapy for non protocol reasons (74% at the close of the study). Participants remained on their allocated treatment for a median of 18 months and the discontinuation rate probably resulted in an underestimate of therapeutic effect. There was no significant difference in the number of adverse events leading to discontinuation of therapy between the combination therapy groups and for ZDV monotherapy. The CAESAR trial (CAESAR is an acronym for the areas that participated i.e. Canada, Australia, Europe and South Africa) was a randomized, controlled double-blind trial to compare the efficacy and safety of the nucleoside analogue 3TC, vs 3TC+loviride vs placebo when added to ZDV containing regimens in patients with HIV disease [6]. All 1840 patients had a CD4 count between 25 and 250×106 l−1, 60% had been treated with ZDV monotherapy and 40% received either ZDV+ddI or ZDV+ddC prior to the study. The primary efficacy outcome was the development of new AIDS defining events or death. The median duration of follow up was 52 weeks. There was a 55% reduction in disease progression or death in the 3TC containing arms (placebo 20%, 3TC 9%, 3TC+loviride 9%P<0.0001). Mortality was also significantly reduced by 50% in the 3TC arms compared with placebo. Subgroup analysis confirmed a significant 54% reduction in disease progression in the 3TC containing arms in patients entering the trial on ZDV monotherapy. patients in the 3TC group hospital or for HIV related The CAESAR study demonstrated the addition of 3TC to ZDV treatment regimens significantly the progression of HIV disease and improved thus further of the benefit of combination therapy in the treatment of HIV disease. In the study for on patients with AIDS or fewer than l−1 CD4 were to ZDV 600 mg daily, ZDV 600 mg+ddI 400 mg daily or ZDV 600 mg+ddC 2.25 mg daily The primary end point was disease progression or death over a median follow up of months. progression or death in of patients treated with ZDV of patients treated with ZDV+ddI and for the ZDV+ddC group. Similarly there was no significant difference in mortality between the groups alone ZDV+ddI ZDV+ddC A analysis did show a benefit for combination therapy in patients who had received ZDV for less than months. Participants in the study had advanced HIV disease CD4 counts between and l−1, over had an AIDS defining and approximately had received prior treatment with effects were more frequent among patients combination therapy. The results of these large randomized trials brought an end to the of ZDV monotherapy (Table therapy with ZDV+ddI or ZDV+ddC is superior to ZDV alone for patients without prior antiretroviral therapy. For patients who are ZDV experienced the addition of ddI or 3TC will mortality and disease progression to AIDS. The addition of to ZDV experienced patients not a clinical The trials also that combination therapy is beneficial for asymptomatic patients with CD4 counts less than 500×106 l−1 and more the of clear benefit of combination therapy in ZDV experienced patients with advanced disease. This finding may be related to the higher viral load among patients with advanced disease and a more emergence of viral The studies also the reduced of the nucleosides with increasing of HIV disease. As a of the clinical trials guidelines for antiretroviral therapy were by the AIDS in The recommended therapy at that time included ZDV in the treatment of HIV infection the introduction of the protease inhibitors in studies demonstrated the protease inhibitors to be anti-HIV drugs e.g. produced a reduction in plasma HIV RNA which was to that produced by the combination of A recent study of patients with advanced HIV disease CD4 count of l−1 demonstrated the of to disease progression and mortality when added to therapy Treatment with a of two nucleosides reduced HIV replication and CD4 cell counts to a greater extent when compared with the two nucleosides ZDV+ddC Similarly the combination had greater antiviral efficacy as compared with When to HIV patients with a CD4 count from to l−1, at least 20 000 copies of HIV RNA ml−1 and previous ZDV monotherapy the therapy HIV RNA below copies ml−1 over the first in of patients vs for the combination The increase in CD4 cell count was also significantly greater in the therapy group vs l−1 These changes in HIV viral load and CD4 cell count for up to 52 weeks. Recent work has on the of clinical the superiority of the drug Treatment with as compared with significantly the progression of HIV disease in patients with 200 CD4 or less and prior ZDV monotherapy. The proportion of patients with disease progression to AIDS or death was lower and mortality reduced in patients therapy The of HIV disease progression and the efficacy of antiretroviral therapy are strongly associated with the plasma level of HIV RNA. changes in plasma HIV RNA predict changes in CD4 cell counts and after treatment with nucleoside analogues Therefore the HIV guidelines for antiretroviral in that the of therapy was to plasma viral load as low as for as as below the hence clinical outcome However some had difficulty with the to therapy combinations of ZDV plus ddI, 3TC or as therapy including a protease is more to the therapeutic The of the AIDS that the is that is most to and maintain plasma HIV RNA levels below the level of i.e. less than 400 copies ml−1 These guidelines are clear in that at this point in time the will of two nucleoside analogues plus a protease with in of potential combinations to be used are shown in When nucleoside analogues an attempt is to and to two nucleosides that are by as these drugs may for the same Therefore combinations including and should be For all the regimens an attempt is to include either ZDV or as these drugs the to a greater extent as compared with other anti-HIV drugs will also be of between The of ZDV to be an predictor of subsequent disease progression and as 3TC is the only nucleoside reported to delay ZDV would that is an 3TC may and ddI efficacy thus ZDV+ddI can be used as therapy. has been demonstrated to be a nucleoside combination and for many clinicians will be the nucleosides of in When which protease to include in a therapy include and drug The of and is however is only which results in low plasma levels in some patients. We have concentrations of below the of ml−1 in of patients and below the in This in the of from the guidelines A new of will be available and this should higher plasma is an important when protease drugs. We have a 28% discontinuation rate for compared with 10% for and 5% for the potential for drug with to of and of this drug a less in therapy regimens The development of among the protease inhibitors is also a and the efficacy of combinations may be by of may for to and among protease inhibitors may a in the and assays of are not currently available for clinical use. The that therapy including a protease may be the of may not be for all patients due to some of the In this the primary recommended is a combination of two nucleosides plus a non nucleoside reverse transcriptase In the trial in and reduced plasma HIV RNA below 20 copies ml−1 in 55% of patients for at least 52 when to patients with CD4 counts between l−1 The study suggests that the of currently available is when with other drugs when the patient is antiretroviral The have e.g. and and are by are to if with protease inhibitors as is an enzyme and is an enzyme The would not be to with nucleoside There are of protease and containing therapy regimens but the extent and duration of HIV RNA to be greater with a protease on protease combinations (e.g. and therapy that a are not to a for these to therapy. For patients who are not for drug regimens but are at of disease progression initiation of nucleoside therapy e.g. is However must be that nucleoside therapy is more used in combination with a protease nucleoside therapy is used then more frequent viral load is to a more treatment if there is significant sustained increase in HIV RNA. A change in the antiretroviral may be due to treatment adverse potential drug or of a For patients who have viral below the of a increase in plasma HIV RNA to greater than to 5000 copies ml−1 is an to change therapy. For patients who had a significant in HIV RNA but not below the of an increase to greater than 5000 to 10 000 copies ml−1 should a treatment change However if patients a substantial reduction in HIV RNA to and their viral load did not fall below the of an approach to therapy would close there is a confirmed substantial the reduction other than viral may to of viral including recent illness and of course non A therapy will HIV RNA within 2 to however for patients with a viral load may not be to of therapy of the decline in HIV RNA. Therefore is not to prematurely a In the of adverse effects that discontinuation of a a number of of the protease should be the adverse is due to a nucleoside analogue then this should be and with the drug responsible for the adverse effects is not then a and of the therapeutic is of the a to drug or to change to an new therapy must be Patients who are currently two nucleosides should be for of treatment the viral load be then the two nucleosides may be with frequent follow up including viral load with a viral load greater than 5000 to 10 000 copies ml−1 should be as therapy and an therapy It is that therapy the HIV RNA level is low will the of antiretroviral a new drug to the viral load below the of The is to change all drugs or at least to include a of two new drugs in the The addition of a drug to a which has is strongly and is to be to monotherapy which will in a more emergence of drug The protease after on protease is It is that between and is thus of will the of the other Using and may not for to The of an is to produce HIV RNA when used in antiretroviral experienced patients. is the combination of to the of by the levels of are enhanced drugs are at the recommended then may be by up to Therefore the of may be reduced and in our experience 200 mg daily may in the of This a reduction in There is change in levels in the of The efficacy and safety of the combination further study, which is of antiretroviral regimens for treatment are shown in When patients with HIV disease the is of HIV replication for as as The availability of sensitive assays for determination of plasma HIV RNA and new anti HIV drugs this The era of ZDV monotherapy is The of for HIV patients is a drug combination consisting of two nucleoside analogues plus a protease This is a therapeutic in a state of may include the of four antiretroviral drugs in are to this