Low-Level Viremia in HIV-1 Infection: Consequences and Implications for Switching to a New Regimen

Abstract

Virologic failure, or the inability to maintain or achieve viral suppression below detectable limits (<50 copies/mL), occurs in some patients with human immunodeficiency virus (HIV)-1 infection, despite being on a potent antiretroviral (ARV) regimen. Current guidelines state that the goal of therapy is to achieve and maintain HIV-1 RNA below detectable levels, with recommendations to switch regimens upon virologic failure based on the adverse consequences of higher degrees of viremia. With the introduction of potent, newer agents, the likelihood of achieving this goal in treatment-experienced patients is growing. Not all patients who experience virologic failure while on therapy suffer from immediate virologic and immunologic decline; some experience persistently low, but detectable, levels of HIV-1 RNA in the range of 50–1000 copies/mL. The threshold at which low-level viremia (LLV) becomes predictive of disease progression varies between studies, although evidence shows that incomplete viral suppression leads to the accumulation of resistance mutations with a concomitant increase in viral replication, reduction in CD4 cell counts, increased risk of virologic progression, and clinical deterioration. Furthermore, with increasing resistance, future treatment options are compromised. Although there are clinical consequences when a patient is maintained on a failing regimen, it may be preferable to delay a switch in therapy if the chance for resuppression is low. With the introduction of new ARVs within existing classes that have shown significant activity against resistant virus, as well as the introduction of two new classes of ARV agents, HIV treatment has entered a new era. The options for constructing regimens active against multidrug-resistant virus have expanded.     

Protease-inhibitor boosting in the treatment-experienced patient

Highly active antiretroviral therapy (HAART) consisting of protease inhibitor (PI)-containing regimens has revolutionized the treatment options for HIV-infected individuals. However, even with successful treatment, virus is not completely eliminated, and virologic failure can occur because of treatment complexity, tolerability and side-effect issues, and suboptimal pharmacokinetics. Ritonavir-boosted PI therapies (i.e. combinations of low-dose ritonavir with a primary PI) can effectively enhance the pharmacokinetics of the primary PI by reducing its first-pass metabolism and postabsorptive clearance, thereby increasing potency. Boosted PI regimens may also simplify treatment by reducing regimen complexity and pill burden. For treatment-experienced patients, the higher PI concentrations achieved with ritonavir boosting may improve activity against PI-resistant virus. This article reviews the principles of PI boosting, its advantages and disadvantages, and the clinical experience with this strategy in treatment-experienced populations.     

A prospective randomized controlled trial of structured treatment interruption in HIV-infected patients failing highly active antiretroviral therapy (Canadian HIV Trials Network Study 164)

OBJECTIVE: To determine prospectively the impact of switching treatment-experienced patients with virologic failure to a salvage regimen with or without a 12-week structured treatment interruption (STI). The primary endpoint was the percentage of patients with a 3-month sustained HIV RNA level <50 copies/mL. METHODS: A randomized, open-label, multicenter trial. At least 2 new antiretroviral (ARV) drugs, based on patient history, were included in the salvage regimen, as determined before randomization and guided by resistance testing. RESULTS: A total of 147 patients were randomized: 79 to the immediate switch (IS) arm and 68 to the STI arm. Success was achieved by 64% in the IS arm and 51% in the STI arm (95% confidence interval for the difference from 5% in favor of STI to 30% in favor of IS). During the STI, the median decrease in CD4 count was 80 cells/mm and the increase in viral load was 0.8 log10 copies/mL. There were no differences in median CD4 cell counts or HIV RNA levels at week 60. Two unrelated deaths (1 in each arm) and 3 AIDS-defining events (in the STI arm) occurred. CONCLUSION: A 12-week STI before the initiation of salvage ARV therapy did not increase the proportion of patients with 3 months of sustained suppression of HIV RNA to <50 copies/mL.     

Cost-effectiveness of enfuvirtide in treatment-experienced patients with advanced HIV disease

OBJECTIVE: Enfuvirtide (ENF) has been shown to improve short-term virologic responses when given to highly treatment-experienced patients with advanced HIV disease. Because of the high cost of ENF compared with other antiretroviral agents, our objectives were to determine the potential long-term clinical impact and cost-effectiveness of ENF in these patients. METHODS: We used a computer simulation model of HIV disease to project life expectancy, quality-adjusted life expectancy, cost, and cost-effectiveness of ENF in treatment-experienced patients. Input data were from the T-20 versus Optimized Regimen Only (TORO) 1 and 2 trials, 2 studies comparing ENF plus an optimized background regimen (OBR) with an OBR alone. RESULTS: ENF plus an OBR increased projected discounted quality-adjusted life expectancy from 45.4 months with an OBR alone to 54.9 months, a difference of 9.5 quality-adjusted life-months. At the current annual ENF cost of US 18,500 dollars per year (in 2001 US dollars), the incremental cost-effectiveness ratio for ENF plus an OBR was US 69,500 dollars per quality-adjusted life-year (QALY) compared with an OBR alone. When 48-week virologic suppression rates for ENF plus an OBR were varied from a 50% reduction to a 250% increase in the suppression rate attributable to ENF, gains in quality-adjusted life expectancy ranged from 4.5 to 25.9 quality-adjusted life-months compared with an OBR alone, with cost-effectiveness ratios ranging from US 97,900 dollars per QALY to US 52,300 dollars per QALY gained. If ENF is continued after the HIV RNA level returns to the pretreatment baseline, the cost-effectiveness ratio increases to US 168,200 dollars per QALY. CONCLUSIONS: In highly treatment-experienced patients, ENF plus an OBR provides substantial gains in quality-adjusted life expectancy compared with an OBR alone. Although ENF plus an OBR is less cost-effective than other commonly used interventions in HIV disease, its use may be justified, given the poor prognosis of these patients and their otherwise limited options for antiretroviral therapy.     

Discontinuation of Enfuvirtide in Heavily Pretreated HIV-Infected Individuals

Abstract

Background: Enfuvirtide was shown to be highly effective in treatment- experienced patients. Data on discontinuation of enfuvirtide and switch to new antiretroviral drugs are scarce. We aimed to evaluate the efficacy and the impact of discontinuing and/or switching enfuvirtide on virologic and clinical parameters in clinical practice. Methods: All HIV-infected individuals participating in the Swiss HIV Cohort Study who were treated with enfuvirtide for at least 4 weeks in combination with an optimized background antiretroviral regimen were included in this study. Results: A total of 151 patients were analyzed. The median baseline CD4 cell count was 108 cells/μL (interquartile range [IQR] 50–206) and HIV RNA was 4.7 log₁₀ copies/mL (IQR 4.1–5.2). Virologic suppression, defined as a viral load below 50 copies/mL at 12 months, was achieved by 57.6% of patients. Overall, a median CD4 cell increase of 121 cells/μL (IQR 50–189) from baseline was noted. Up to 50% of patients discontinued enfuvirtide within the first year of treatment, mainly because of the patient’s choice. After discontinuation of enfuvirtide, high rates of virologic failure and clinical progression were observed, notably when CD4 cell count at stopping enfuvirtide was below 100 cells/μL and no switch to new potent antiretroviral drugs such as darunavir, maraviroc, or raltegravir was performed. Conclusions: Enfuvirtide provides high virologic and immunologic response in treatment-experienced patients in the setting of clinical practice. Enfuvirtide should not be discontinued but should be replaced by new potent antiretrovirals, particularly in case of severe immunosuppression.     

Virological and Immunological Response to HAART Therapy in a Community-Based Cohort of HIV-1-Positive Individuals

Abstract

Purpose: To determine virological and immunological response to highly active antiretroviral therapy (HAART) and to investigate factors influencing response in a community-based setting. Method: Plasma HIV RNA levels and CD4 cell counts were studied in 168 unselected individuals starting HAART including indinavir or ritonavir or hard-gel saquinavir-containing regimens. Results: Overall, 60% of the patients reduced their HIV RNA to below 500 Eq/mL, but half of them experienced a subsequent virologic rebound. Patients with higher baseline HIV RNA, higher baseline CD4 cell count, and simultaneous initiation of combination therapy and patients on indinavir or ritonavir regimen were more likely to have virologic response within 6 months since HAART initiation. Patients with lower baseline CD4 cell count and with lower rates of viral clearance had a higher probability of a subsequent virologic rebound. Forty percent of the patients had increased their CD4 cell counts by more than 100 cells/μL (immunologic response). The probability of immunologic response was independent of baseline HIV RNA levels and CD4 cell count; however, the more complete the virologic suppression, the higher the probability of immunologic response. Thirty percent of the patients had discordance between virologic and immunologic responses. Conclusion: The rate of virologic failure in this unselected group of patients was higher than that observed in randomized clinical trials, but only a minority (11%) of the patients were treatment naïve. Starting combination therapy simultaneously and initiating antiretroviral therapy before advanced HIV disease has developed predict virologic response, whereas the magnitude of viral suppression predicts mid to long immunological response.     

Antiretroviral therapy in the treatment-experienced patient

Despite the growing number of new antiretroviral agents, planning therapy for treatment-experienced patients remains extremely challenging. Cross-resistance within the three currently available classes of drugs limits the number of sequential drug regimens that can be expected to suppress viral replication effectively. An understanding of resistance and cross-resistance, together with judicious use of resistance testing, can help clinicians design better treatment regimens for patients experiencing virologic failure while taking antiretroviral therapy.     

Once-daily therapies for the treatment of HIV infection

For patients initiating antiretroviral therapy, there are several well-tolerated once-daily regimens from which to choose. Once-daily antiretroviral therapy may be ideal for patient adherence and convenience. However, results of a few recent clinical trials exploring new once-daily regimens have shown that one cannot assume that any three-drug combination will be successful. Once-daily therapy options for treatment-experienced patients are more limited but may be successful depending on prior antiretroviral treatment exposure and resistance mutations. Current approaches to once-daily therapy include simplifying successful regimens and investigating novel antiretroviral agents with long half-lives.     

Strategies for overcoming resistance in HIV-1 infected patients receiving HAART

Highly active antiretroviral therapy (HAART) has fundamentally changed the clinical outcome of HIV infection and AIDS. However, the emergence of drug-resistant HIV variants is a barrier to successful use of HAART, with resistance to one drug often resulting in cross-resistance to many, if not all, others in the same class. The rise in the incidence of drug-resistant variants among newly infected patients also represents a formidable challenge for clinicians. Failure of the current HAART regimen due to drug resistance can severely limit second-line, third-line, and salvage treatment options. Although inadequate exposure of the virus to antiretroviral agents is a prime reason for the emergence of HIV drug-resistant variants, poor adherence to complicated regimens and variability in drug pharmacokinetics (PK), both within and between HIV-infected individuals, can also affect the overall efficacy of antiretroviral agents, promoting emergence of resistant HIV variants. Recent strategies to optimize antiretroviral drug regimens, including assessment of HIV genotype and/or phenotype, the use of protease inhibitor regimens that incorporate PK boosting, and scheduled treatment interruptions, have been explored. Additionally, several newer antiretroviral agents that produce rapid and sustained virologic and immunologic responses as well as novel resistance profiles (e.g. atazanavir and tenofovir) have become available. These characteristics thus increase the likelihood of durable viral suppression.     

Management of HIV-infected patients with multidrug-resistant virus

Treatment-experienced patients with HIV may harbor virus that has accumulated several mutations conferring decreased susceptibility to one or more antiretroviral drugs. For clinicians treating these patients, identifying a tolerable antiretroviral regimen with a reasonable chance of a durable virologic effect represents a major challenge. The first priority is to identify and correct the mechanisms responsible for previous treatment failure. Resistance testing and drug level monitoring may be useful in this setting. The patient’s history of antiretroviral drug tolerability, comorbidities, and concomitant medications should be considered. Patients embarking on multiple-drug regimens will require close monitoring for adherence, toxicities, and drug-drug interactions. The guiding principle when constructing a rescue or salvage regimen is to achieve a cumulative activity score greater than 2, recognizing that some agents will have only partial activity. Some new drugs are available that may be helpful if used carefully with an active background regimen.     

Predictors of successful genotype-guided antiretroviral therapy in treatment-experienced individuals over calendar years: A cohort study

BackgroundThe continuous development of new drugs for use in triple-drug combination antiretroviral therapy (cART) has dramatically decreased morbidity and mortality in HIV-1 infected individuals. However, increasing drug resistance could be associated with a poor outcome.ObjectivesTo determine the efficacy of resistance genotype-guided antiretroviral regimens in combination antiretroviral therapy (cART)-failing patients over calendar years and its predictors.Study designPatients, with an available resistance genotype performed between 1999 and 2008, who failed a highly active antiretroviral therapy (HAART) regimen, changed therapy within 6 months from genotype and maintained the same salvage regimen, were selected from a clinical cohort database. Virologic efficacy was analyzed using time-to virologic suppression (VS, HIV-1 RNA < 50 copies/ml).ResultsIn 270 sequences analyzed from 212 patients, after a median follow-up of 23 weeks, there were 160 patients with VS (59.3%). Mean regimens’ genotypic sensitivity score (GSS) increased from 1.86 (SD ± 0.92) in 1999–2001, to 2.29 (SD ± 0.96) in 2005–2008 (p = 0.001 for trend). VS was achieved in 39% of those patients genotyped in 1999–2001, and increased to 69% for patients with genotyping performed between 2005 and 2008 (p < 0.001). More recent calendar year, younger age and less use of suboptimal therapy were predictors of more effective HAART regimens but only more recent calendar year maintained a trend toward significance in a multivariable model. More recent genotyping calendar year, younger age, lower number of HAART regimens experienced, lower HIV-1 RNA and higher GSS independently conveyed and increased the probability of VS.ConclusionsResistance-guided salvage antiretroviral therapy was more effective during more recent calendar years, independent from other measurable confounders, including the GSS of the employed regimen. Convenience and tolerability of newer agents should account for the observed effect.     

Psychiatric illness and virologic response in patients initiating highly active antiretroviral therapy

BACKGROUND: Mental illness (MI) and substance abuse (SA) are common in HIV-positive patients. MI/SA consistently predict poorer antiretroviral adherence, suggesting that affected patients should be at higher risk of poor virologic and immunologic response to highly active antiretroviral therapy (HAART). PARTICIPANTS: 198 HAART-naive patients initiated HAART at an academic medical center serving a heterogeneous population. METHODS: Participants were assigned a predicted probability from 0 to 1 of having each of the following: (1) any mood, anxiety, or substance use disorder; (2) clinically relevant depression; (3) alcohol abuse/dependence; and (4) drug abuse/dependence. Probabilities were based on responses to questions on an MI/SA screening instrument (Substance Abuse and Mental Illness Symptoms Screener [SAMISS]) and other clinical and sociodemographic characteristics and were derived using predictive logistic regression modeling from a separate validation study of the SAMISS compared with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnoses. Using survival analysis techniques, we assessed baseline predicted probability of psychiatric illness as a predictor of time from HAART initiation to virologic suppression (first viral load [VL] <400 copies/mL), from HAART initiation to overall virologic failure (first VL >or=400 copies/mL after suppression, time set to 0 for patients never achieving suppression), from virologic suppression to virologic rebound (first VL >or=400 copies/mL), and from HAART initiation to immunologic failure (first CD4 cell count lower than baseline). RESULTS: A higher predicted probability of any psychiatric disorder was associated with a slower rate of virologic suppression (adjusted hazard ratio [aHR] = 0.86 per 25% increment, 95% confidence interval [CI]: 0.75 to 0.98) and a faster rate of overall virologic failure (aHR = 1.22, 95% CI: 1.06 to 1.40). Associations with other outcomes were consistent in direction but not statistically significant. Predicted probability of depression was associated with slower virologic suppression (aHR = 0.79, 95% CI: 0.63 to 0.98), and predicted probabilities of alcohol and drug abuse/dependence was associated with faster overall virologic failure (aHR = 1.37, 95% CI: 1.08 to 1.74 and aHR = 1.18, 95% CI: 1.00 to 1.39, respectively). CONCLUSIONS: These results are consistent with an inferior virologic response to first HAART among patients with concurrent mood, anxiety, and substance use disorders, suggesting a clinical benefit to identification and treatment of psychiatric illness among patients initiating antiretroviral therapy.     

International perspectives on antiretroviral resistance. Clinical utility of resistance testing: retrospective and prospective data supporting use and current recommendations

Data from retrospective and prospective studies support use of genotypic and phenotypic resistance assays to guide treatment changes when initial or subsequent antiretroviral regimens fail. Several retrospective studies have shown that response to antiretroviral therapy can be predicted based on genotypic analysis of HIV, with baseline genotypic evidence of resistance predicting virologic failure. Other retrospective analyses demonstrated that phenotypic drug sensitivity correlates with increased viral load suppression, particularly when virus remains sensitive to two or three drugs at initiation of the regimen. Furthermore, prospective studies such as VIRADAPT and Genotype-Assisted Antiretroviral Resistance Testing (GART) have substantiated that drug selection based on genotypic assay results yield superior viral suppression compared with empiric treatment assignment. One additional study suggested significant improvement in short-term virologic outcome when phenotypic testing was used to guide treatment selection. Based on these findings, resistance testing is currently recommended for patients with acute HIV infection, those who have failed one or more antiretroviral regimens, and pregnant women. Although these tests move toward becoming a standard of care, several research questions remain: the long-term benefit of resistance testing is not yet certain, the interpretation of specific genotypic resistance patterns needs to be better defined, and clinical cut-off points for phenotypic resistance need to be established. As these issues continue to be studied, resistance testing likely will prove a reliable tool to help plan successful ART strategies.