HAART: How Good is Good Enough?
Synopsis: The "decay" in HIV viremia during the first week of therapy can predict longer-term response and is similar for all responders.
Source: Polis MA, et al. Correlation between reduction in plasma HIV-1 RNA concentration 1 week after start of antiretroviral treatment and longer-term efficacy. Lancet. 2001; 358:1760-1765.
The measurement of plasma HIV-1 RNA has provided a useful marker of the risk of HIV progression and response to antiretroviral therapy. The current US Department of Health Human Services guidelines suggest that consideration be given to augmentation of therapy or a change in the regimen if there has not been at least a 0.5-0.75 log reduction by 4 weeks of therapy or at least a 1.0 log reduction by 8 weeks.1 Polis and colleagues examined the relationship between the kinetics of the virologic response to therapy as early as 1 week after initiation of treatment and virologic outcome, as defined by the DHHS guidelines, at 4 and 8 weeks. Three groups of patients were examined, including 52 children who were protease inhibitor-naïve who received indinavir monotherapy, 38 children who were protease inhibitor-naïve who received ritonavir monotherapy, and 34 adults who received a 4-drug combination regimen of AZT, 3TC, indinavir, and nevirapine. There were no significant differences between the groups with regard to CD4 cell counts and plasma viral load.
A one-exponential model was used to determine the coefficient of decay (k) for each of the 3 groups. All 34 patients receiving HAART had a good response to therapy, as defined by the current guidelines, with a mean decay constant = 0.26 at 1 week. Far fewer patients had a good response to ritonavir monotherapy (34%) or indinavir monotherapy (7.7%). However, for those that were considered responders, the average decay constants were 0.24 and 0.21, respectively, after 1 week of ritonavir or indinavir monotherapy, which were similar to that for patients receiving HAART. In other words, the dynamics of the HIV decay in response to 1 week of treatment was similar for all responders, irrespective of the specific agent, or agents, received.
A cut-off value of k > 0.21 per day was predictive of a good response to therapy at 8 weeks with a sensitivity of 0.85, a specificity of 0.82, and a predictive value of 0.87. Using the decay constant as a predictive model, there was a 95% or greater chance of virologic failure at week 8 with a viral load response < 0.96 at 1 week of therapy, and a 95% or better chance of success with a viral load response > 1.68 at 1 week of therapy.
Because this analysis was only performed in patients naïve to the type of therapy received, these results may not apply to more ART experienced patients or those who have pre-existing mutations. Theoretically, the initial HIV dynamics for patients with archived mutations who have a predominance of circulating wild-type virus following a treatment interruption may show a similarly immediate response to therapy. However, the decay constant during the first week of therapy may fail to predict the emergence of drug resistant mutants in response to selective pressure by as early as 8 weeks of therapy. Nonetheless, this data may be very useful in patients who are treatment naïve or who are naïve to the class of drugs received. —cak
Hepatic Injury to HAART
Synopsis: Liver function test abnormalities are frequent in HAART but should not lead to discontinuation of therapy in most patients.
Source: Nuñez M, et al. Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2001;27:426-431.
Nuñez and colleagues in Madrid, Spain, determined the frequency of hepatic injury in 222 HIV-infected treatment-naïve patients beginning their first HAART regimen. Elevations in hepatic transaminases that were considered significant were ³ 5 times the upper limit of normal, or ³ 3.5-fold rise above abnormal baseline values. Patients received a variety of antiretroviral regimens either containing a protease inhibitor (43%), an NNRTI (40.5%), or both (15.8%). The groups were similar with respect to stage of HIV, CD4 cell counts, frequency of abnormalities in transaminases, and prevalence of hepatitis C (38%), chronic hepatitis B (5%), or D (2%).
Overall, 21 of 222 (9%) patients experienced severe elevations in hepatic transaminases, the frequency of which was similar for patients receiving a PI, an NNRTI, or both. In patients receiving either a single PI or an NNRTI, severe hepatic injury occurred, in decreasing order of frequency, with ritonavir (18%), saquinavir (14%), nevirapine (11%), nelfinavir (10%), indinavir (9%), and efavirenz (6%). Fortunately, most of these more severe laboratory test abnormalities were transient, and had resolved within 1 to 2 months in 75% of patients despite continuation of therapy. Only 6% of subjects discontinued or changed their regimen because of hepatic toxicity.
In multivariate analysis, the presence of chronic hepatitis C infection was the most significant factor predictive of hepatic injury, followed by alcohol abuse and older age. Elevations in hepatic enzymes were 3 times as frequent in patients with underlying HCV infection vs. HCV-negative patients (16% vs 5%). They were also 3 times more frequent in patients with chronic HBV infection. The shift in the paradigm for initiating HAART at lower CD4 cell counts provides a window of opportunity to first treat chronic HCV infection, thereby possibly reducing the potential for subsequent HAART treatment toxicity. In addition, Nuñez et al point out that more attention to alcohol consumption when starting HAART, and more aggressive alcohol counseling, may further reduce the potential for toxicity. Although more severe liver function test abnormalities are frequent (6-18%) in patients initiating HAART, they do not often require a change in therapy, and are resolved in most patients without serious sequelae. —cak
Enhanced Susceptibility to Amprenavir
Synopsis: "Hypersusceptibilty" and enhanced virologic response to amprenavir-based antiretroviral therapy may be associated with the presence of an N885 mutation in the protease gene.
Source: Zachary KC, et al. Human immunodeficiency virus type 1 hypersusceptibility to amprenavir in vitro can be associated with virus load response to treatment in vivo. Clin Infect Dis. 2001;33:2075-2077.
Sequencing of protease inhibitor therapy in response to the emergence of resistant HIV virus is critical to the success of an overall treatment strategy for patients with HIV infection. Recognized patterns of cross-resistance in patients failing a protease inhibitor are helpful in estimating the likelihood of response to therapy, although the specific pattern of susceptibility for any one individual is difficult to predict from treatment history alone without the benefit of genotypic and phenotypic resistance assays. Phenotypic resistance data also provide important information on the magnitude of susceptibility, including whether an isolate may have enhanced susceptibility to a particular agent ("hypersusceptibility"), which may have important therapeutic implications.
Data suggest that the N88S protease gene mutation, which is occasionally observed in patients failing indinavir and nelfinavir, may confer enhanced susceptibility to amprenavir.2 Zachary and colleagues report a case of an HIV-positive man who had previously failed first indinavir and then nelfinavir for 2 years, with evidence of amprenavir hypersusceptibility and a remarkably sustained virologic response to an amprenavir-containing regimen. Following failure to nelfinavir, a genotypic resistance assay revealed multiple thymioine associated mutations (TAMs) plus several protease mutations (L10I, I64V, V77I, and N88S). The corresponding phenotype indicated the following fold changes: abacavir (2.1), D4T (1.7), amprenavir (0.1), ritonavir (0.6), and nelfinavir (14.6). [Fold change = the concentration of drug required to inhibit viral replication by 50% (IC50) compared with control (wild type virus) (IC50 patient/IC50 control), (PhenoSenseÔ HIV Assay, ViroLogic Inc., South San Francisco, Calif)]. Based on this information, the patient received a combination of D4T, abacavir, amprenavir 750 mg b.i.d., and ritonavir 400 mg b.i.d. with a resulting sustained virologic response for more than 2 years (HIV RNA < 50 copies/mL).
Based on this individual’s history of failure to first indinavir and then nelfinavir, he was likely to have significant cross-resistance among the protease inhibitors, although prior mutations as the result of indinavir failure may have been "archived" and not phenotypically evident. In our study of patients failing ART therapy who had mostly been treated with nelfinavir- or indinavir-containing regimens,3 the majority retained virus with a drug-sensitive phenotype (FC < 2.5) to amprenavir or saquinavir (lobucavir susceptibility was not assessed at that time). HIV isolates from 55 patients failing nelfinavir commonly remained susceptible (FC < 2.5) to ritonavir (84%) and amprenavir (93%), whereas HIV isolates obtained from 22 patients failing indinavir less often remained susceptible to ritonavir (36%) and amprenavir (54%). Furthermore, we found that in patients failing nelfinavir, the mean fold change in IC50 to ritonavir was 2.3, and to amprenavir was 1.1.
A cut-off fold change smaller than 0.4 is believed to confer hypersusceptibility, although the clinical significance of this finding is still being explored. In addition, based on an increasing amount of data, a fold change of > 1.7 has been proposed for D4T resistance. Therefore, this man had evidence of significantly enhanced susceptibility to amprenavir but reduced susceptibility to D4T. Although the contribution of each PI to the regimen in this case is not known, the administration of ritonavir-boosted amprenavir in the presence of known hypersusceptibility, possibly associated with the N88S mutation, may have been important to the long-term success of this regimen.
Dr. Kemper, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, is Associate Editor of Infectious Disease Alert.
References
1. US Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Washington, DC: DHHA, 2001. http://hiv.medscape.com/govmt/DHHS/guidelines/HIV/HIV-01.html.
2. Ziermann R, et al. J Virol. 2000;74: 4414-4419.
3. Kemper CA, et al. AIDS. 2001;15:609-615.
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