Durable Virologic Suppression Research Articles

Novel clinical trial designs for the development of new antiretroviral agents

We thank Dunn et al.[1] for their comments on our article. The article [2] reports an expert discussion on antiretroviral drug development at a time when the great majority of patients, including most who have experienced virological failure once or more, have licensed treatment options that if, adhered to, will help achieve durable virological suppression. As discussed in the article, traditional large-scale comparative trials like those pivotal for the licensure of raltegravir or etravirine are therefore difficult to conduct. There remains, however, a small group of patients for whom a likely suppressive treatment regimen may not be available, and for whom new agents that are efficacious against viral strains with multiple resistances to existing drugs would be of value. Due to the relative scarcity of patients without remaining treatment options, and to the recognized risk of aggravating drug resistance with incompletely suppressive regimens, drug development in this population is a challenge. As a first point of response to the comment by Dunn et al. [1], we note that the proposed study design discussed at the meeting principally addresses a population that would not be recommended for study in traditional 24–96 week placebo controlled trials according to present European or US regulatory and clinical guidance [3,4]. Dunn et al. [1] question whether the efficacy assessment in the proposed study adds value, over and above that obtained in phase 1/2 dose ranging monotherapy studies. In this context, we note that investigational agents that might be studied according to the proposed design are most likely to be new agents of existing drug classes. Thus, the primary efficacy objective of the randomized phase would be to assess in-vivo antiviral potency against a range of viruses with different genotypic resistance mutation patterns relevant to the drug class, and possibly conferring cross resistance to the new agent. Traditional monotherapy dose-ranging studies are generally performed in treatment-naive patients, and this information would not be obtained in such studies. If ‘functional’ monotherapy (add-on) studies in drug-class experienced patients failing their present regimen were performed in phase 1/2, these might be designed as smaller, pilot-type studies of a similar design as the randomized phase of the proposed pivotal study. Dunn et al. [1] rightly note that the proposed study would not provide randomized evidence of the durability of response. In this context, an assumption of the rationale for the proposed design is that, if an antiretroviral drug showed reasonable short-term potency against a certain viral resistance strain, available experience indicates that it would be highly likely to contribute to the long-term durability of response to a combination regimen, provided that the other agents had different mechanisms of action and did not select for similar drug resistance mutations. The second, nonrandomized phase of the proposed study would provide observational data on the durability of response, to be analyzed in relation to estimated optimized background therapy activity. Furthermore, it would provide information on emerging resistance mutations to the new agent in case of failure. As was discussed at the meeting, in order to generate randomized comparative data on the contribution of the new agent to the durability of response, the agent could be investigated in traditional, reasonably sized studies, which would likely have a noninferiority design. The meeting deliberations, which were prompted by the present treatment landscape, noted that such studies would most readily be conducted in treatment naive or lightly treatment experienced patients. Also, in such studies, rates of emerging drug resistance in case of viral failure would provide valuable information on the barrier to resistance of the agent. Finally, Dunn et al. [1] pose valid questions concerning the lack of randomized evidence on safety with the proposed study design. Neither the meeting nor our report systematically covered the issue of what supporting safety data would be required to bring a drug to market in the context of pivotal trials of the kind proposed. The size of the safety database, as well as the trials in which this may be generated, may differ depending on the range of treatment populations that are targeted in the drug development program. This will need to be further defined by regulatory agencies, if the proposed path is followed. Acknowledgements Conflicts of interest There are no conflicts of interest.

Etravirine

Etravirine (Intelence®) is an orally administered next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI). It is approved for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and are harbouring HIV-1 strains resistant to other antiretroviral (ARV) agents. In the US, etravirine must be used in combination with other ARV agents; in the EU, it must be used in combination with other ARV agents that include a boosted HIV-1 protease inhibitor. Etravirine shows good activity in vitro against most wild-type strains of HIV-1, as well as against several strains resistant to available NNRTIs. Furthermore, etravirine appears to present a higher barrier than first-generation NNRTIs against the development of drug resistance. Whereas the presence of a single mutation is sufficient to affect the virological response to efavirenz or nevirapine, the resistance profile of etravirine is more complex and a prediction of virological response may be calculated using a weighted genotypic score. Importantly, the most prevalent NNRTI-associated mutation, K103N, alone does not affect the etravirine response. In two identically designed randomized clinical trials, the addition of etravirine to an optimized background therapy (OBT) regimen improved virological responses to a greater extent than placebo plus OBT following 24 weeks' treatment in highly treatment-experienced adult patients with HIV-1 infection who had evidence of viral replication (HIV-1 RNA levels of >5000 copies/mL at baseline). Furthermore, pre-planned pooled analyses of the trials at 48 and 96 weeks showed that etravirine plus OBT provided durable virological suppression. Consistently higher virological response rates were observed for recipients of etravirine plus OBT than placebo plus OBT in a pre-specified subgroup analysis of baseline viral loads, CD4+ cell counts, HIV-1 subtype or the composition of background ARV therapy. Greater improvements from baseline in immunological outcomes were also observed for recipients of etravirine plus OBT compared with those receiving placebo plus OBT over the 96-week treatment period of the trials. When used as part of an OBT regimen in trials of up to 96 weeks duration, etravirine was well tolerated with an overall tolerabilty profile similar to that of placebo. The only treatment-emergent adverse event that occurred with a higher frequency for recipients of etravirine compared with placebo plus OBT was rash. In highly treatment-experienced patients with HIV-1 infection and evidence of viral replication, the addition of etravirine to an OBT regimen provides an effective and well tolerated treatment that leads to improvements in both virological and immunological outcomes.

Elvitegravir: a once-daily inhibitor of HIV-1 integrase

Introduction: Elvitegravir (EVG) is a potent inhibitor of HIV-1 integrase (IN) undergoing Phase III clinical trials. It blocks the strand-transfer step in a multi-step process that allows double-stranded cDNA to be irreversibly incorporated within the host DNA. It is the second member of the HIV-1 IN inhibitor class, following raltegravir. Co-administration with a CYP3A inhibitor, such as ritonavir or cobicistat, substantially increases EVG plasma exposure and prolongs elimination half-life.Areas covered: A Medline review of Phase II and III trials involving EVG as well as a review of abstracts from major HIV and infectious disease conferences from 2010 to 2011 was conducted. EVG produces rapid and durable virologic suppression when combined with active background therapy. Trials investigating the efficacy of once-daily co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) demonstrate a high rate of virologic suppression with fewer CNS and psychiatric adverse events compared with co-formulated efavirenz/emtricitabine/tenofovir. The resistance profile for EVG is similar to raltegravir.Expert opinion: Co-formulated EVG/COBI/FTC/TDF is an option for the treatment of antiretroviral naïve and experienced patients. Once-daily dosing offers an advantage over raltegravir, but the requirement for pharmacologic boosting increases regimen complexity. Dolutegravir in development offers a favorable resistance profile and no requirement for pharmacologic boosting.

HIV-Associated Neurological Disorders

In the era of highly active antiretroviral therapy (HAART), HIV-1-associated neurocognitive disorder (HAND) continues to be a common and significant morbidity among individuals infected with HIV. The term HAND encompasses a spectrum of progressively severe CNS involvement, ranging from asymptomatic neurocognitive impairment and minor neurocognitive disorder through to the most severe form of HIV-associated dementia (HAD). While the incidence of HAD has declined significantly with HAART, the milder forms of HAND persist. In addition, HAND now develops in individuals with less advanced immunosuppression. The reasons for the persistence of milder forms of HAND in individuals treated with HAART are not entirely known. There are several hypotheses to explain this phenomenon that include the legacy effect, a failure of antiretroviral agents to reverse neurological damage, poor access of antiretroviral agents to the CNS, chronic systemic immune activation associated with microbial translocation products, sustained CNS inflammation, the improved survival of HIV-seropositive individuals and the possible contribution from aging, amyloid deposition and other co-morbidities. In contrast, the incidence of HIV-associated CNS opportunistic processes including progressive multifocal leukoencephalopathy, tuberculosis, CNS toxoplasmosis, cytomegalovirus encephalitis, cryptococcosis and primary CNS lymphoma has declined dramatically with the introduction of HAART. This review briefly summarizes our current understanding of HAND and the pathological mechanisms involved, namely direct injury from HIV-1 and viral proteins, indirect neurotoxicity from proinflammatory cytokines and chronic, sustained immune activation in the CNS. To date, only HAART has been shown to benefit HAND despite numerous controlled trials of adjunctive 'anti-inflammatory' agents. Although HAART has a profound impact on the incidence and severity of HAND, there exists a 'therapeutic gap' as even HAART that is effective at inducing durable virological suppression may only partially reverse HAND. In addition, there may be potential CNS adverse effects of antiretroviral agents. There is an ongoing multicentre clinical trial to investigate the role of the CNS Penetration-Effectiveness index, an indicator of drug permeability and availability in the CNS, to help guide the choice of antiretroviral agents in the treatment of HAND. With recent recommendations for earlier treatment intervention with HAART for HIV-1 infection, it remains to be seen the effects of this on HAND. There is an urgent need to better define the therapeutic guidelines for the prevention and treatment of HAND.

Novel use of surveillance data to detect HIV-infected persons with sustained high viral load and durable virologic suppression in New York City.

BackgroundMonitoring of the uptake and efficacy of ART in a population often relies on cross-sectional data, providing limited information that could be used to design specific targeted intervention programs. Using repeated measures of viral load (VL) surveillance data, we aimed to estimate and characterize the proportion of persons living with HIV/AIDS (PLWHA) in New York City (NYC) with sustained high VL (SHVL) and durably suppressed VL (DSVL).Methods/Principal FindingsRetrospective cohort study of all persons reported to the NYC HIV Surveillance Registry who were alive and ≥12 years old by the end of 2005 and who had ≥2 VL tests in 2006 and 2007. SHVL and DSVL were defined as PLWHA with 2 consecutive VLs ≥100,000 copies/mL and PLWHA with all VLs ≤400 copies/mL, respectively. Logistic regression models using generalized estimating equations were used to model the association between SHVL and covariates. There were 56,836 PLWHA, of whom 7% had SHVL and 38% had DSVL. Compared to those without SHVL, persons with SHVL were more likely to be younger, black and have injection drug use (IDU) risk. PLWHA with SHVL were more likely to die by 2007 and be younger by nearly ten years, on average.Conclusions/SignificanceNearly 60% of PLWHA in 2005 had multiple VLs, of whom almost 40% had DSVL, suggesting successful ART uptake. A small proportion had SHVL, representing groups known to have suboptimal engagement in care. This group should be targeted for additional outreach to reduce morbidity and secondary transmission. Measures based on longitudinal analyses of surveillance data in conjunction with cross-sectional measures such as community viral load represent more precise and powerful tools for monitoring ART effectiveness and potential impact on disease transmission than cross-sectional measures alone.

Treatment Failure in Children with HIV

Maintaining durable virologic suppression is critical for all HIV-infected patients, but particularly so for children, who require lifelong

Lopinavir: the Old Champion

Lopinavir/ritonavir approval for use in antiretroviral treatment 10 years ago was very important for the recognition of boosted protease inhibitor (PI)-based therapy as an attractive option for first-line therapy. Being coformulated with ritonavir and having less toxicity than former PIs it allowed for effective and durable virologic suppression with less impact on quality of life. It soon became the standard of care for salvage therapy in its class. Since then, however, its central role has been challenged by new PIs with a more favorable impact on lipid profile, better gastrointestinal tolerability or that are more active in the setting of multidrug resistance. This article summarizes the main clinical studies with lopinavir and discusses its particular characteristics as well as its possible current role in antiretroviral therapy.

Vitamin D Supplementation and Endothelial Function in Vitamin D Deficient HIV-Infected Patients: A Randomized Placebo-Controlled Trial

Studies suggest that vitamin D deficiency is a risk factor for cardiovascular disease and diabetes. Vitamin D deficiency is prevalent in HIV patients but the effect of vitamin D supplementation on cardiovascular risk in this population is unknown. We conducted a randomized, double-blind, placebo-controlled trial among 45 HIV-infected adults in Cleveland (OH, USA) on stable antiretroviral therapy with durable virological suppression and a baseline serum 25-hydroxyvitamin D level of ≤20 ng/ml. Participants were randomized 2:1 to vitamin D3 4,000 IU daily or placebo for 12 weeks. The primary outcome was a change in flow-mediated brachial artery dilation (FMD). Baseline demographics were similar except for age (vitamin D versus placebo, mean ±sd 47 ±8 versus 40 ±10 years; P=0.009). Both groups had reduced FMD at baseline (median values 2.9% [IQR 1.6-4.8] for vitamin D versus 2.5% [IQR 1.7-6.4] for placebo; P=0.819). Despite an increase in the concentration of serum 25-hydroxyvitamin D from baseline to 12 weeks (5.0 ng/ml [IQR -0.9-7.4] versus -1.9 ng/ml [IQR -4.0-0.1] for vitamin D versus placebo, respectively; P=0.003), there was no difference in FMD change (0.55% [IQR -1.05-2.13] versus 0.29% [IQR -1.61-1.77]; P=0.748). Vitamin D supplementation was associated with a decrease in total and non-high-density lipoprotein cholesterol, and an increase in indices of insulin resistance. Among HIV-infected individuals with vitamin D deficiency, supplementation with 4,000 IU vitamin D3 daily for 12 weeks modestly improved vitamin D status and cholesterol but worsened insulin resistance without change in endothelial function. The mechanisms of resistance to standard doses of vitamin D and the complex role of vitamin D in glucose metabolism in this population require further investigation.

Long-Term Treatment With Entecavir Induces Reversal of Advanced Fibrosis or Cirrhosis in Patients With Chronic Hepatitis B

Long-term treatment with entecavir resulted in durable virologic suppression and continued histologic improvement in nucleoside-naive chronic hepatitis B patients. Patients with advanced fibrosis or cirrhosis, who received long-term entecavir treatment, were evaluated for improvement in liver histology. The study included a subset of patients from phase III and long-term rollover studies, who received entecavir for at least 3 years, had advanced fibrosis or cirrhosis, and evaluable biopsies at baseline and after long-term treatment. Ten patients had advanced fibrosis or cirrhosis at baseline (Ishak fibrosis score, ≥ 4). After approximately 6 years of cumulative entecavir therapy (range, 267-297 wk), all 10 patients showed improvement in liver histology and Ishak fibrosis score. The mean change from baseline in Ishak fibrosis and Knodell necroinflammatory scores were -2.2 and -7.6, respectively. A reduction in Ishak fibrosis score to 4 or less was observed for all 4 patients who had cirrhosis at baseline. Chronic hepatitis B patients with advanced fibrosis or cirrhosis demonstrated histologic improvement and reversal of fibrosis and cirrhosis after long-term treatment with entecavir.

Lopinavir/Ritonavir

Lopinavir/ritonavir (Kaletra®) is an orally administered coformulated ritonavir-boosted protease inhibitor (PI) comprising lopinavir and low-dose ritonavir. It is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults, adolescents and children. Lopinavir/ritonavir is available as a tablet, soft-gel capsule and an oral solution for patients with difficulty swallowing. In well designed, randomized clinical trials, lopinavir/ritonavir, in combination with other antiretroviral therapies (ART), provided durable virological suppression and improved immunological outcomes in both ART-naive and -experienced adult patients with virological failure. Furthermore, lopinavir/ritonavir demonstrated a high barrier to the development of resistance in ART-naive patients. More limited data indicate that it is effective in reducing plasma HIV-1 RNA levels in paediatric patients. Lopinavir/ritonavir has served as a well established benchmark comparator for the noninferiority of other ritonavir-boosted PI regimens. Although generally well tolerated, lopinavir/ritonavir is associated with generally manageable adverse gastrointestinal side effects and hypertriglyceridaemia and hypercholesterolaemia, which may require coadministration of lipid-lowering agents to reduce the risk of coronary heart disease. Lopinavir/ritonavir, in combination with other ART agents, is a well established and cost-effective treatment for both ART-naive and -experienced patients with HIV-1 infection and, with successful management of adverse events, continues to have a role as an effective component of ART regimens for the control of HIV-1 infection.

Efficacy and Tolerability of Zidovudine 200 mg Twice a Day as Part of Combination Antiretroviral Therapy for 96 Weeks

Efficacy and Tolerability of Zidovudine 200 mg Twice a Day as Part of Combination Antiretroviral Therapy for 96 Weeks

Improvements in Subcutaneous Fat, Lipid Profile, and Parameters of Mitochondrial Toxicity in Patients with Peripheral Lipoatrophy When Stavudine is Switched to Tenofovir (LIPOTEST Study)

Background: Lipoatrophy is the most stigmatizing side effect of stavudine therapy. We assessed the long-term effects of replacing stavudine with tenofovir in HIV-infected patients with lipoatrophy. Method: Prospective switch study. Sixty-two clinically stable patients with antiretroviral therapy (ART) containing stavudine, HIV-1 RNA <50 copies/mL, and lipoatrophy at least in the face on physical examination were included. All patients switched from stavudine to tenofovir without changing any other drug. Objective (malar ultasonography, bioelectrical impedance analysis) and subjective measures of lipoatrophy were assessed. Results: Median age at baseline was 40 years, 44 patients (71%) were male, and median time on stavudine was 4.8 years. Median malar fat thickness increased 0.8 mm (25%) 24 months after switching. Total fat mass increased 3.9 kg (21%). Plasma lactate levels decreased significantly, mainly in patients with baseline hyperlactatemia (from 3.05 to 1.19 mmol/L). Significant improvement in total cholesterol (−12%), triglycerides (−31%), and total cholesterol/HDL cholesterol ratio (−11%) was observed at Month 24. Conclusions: In this study, switching from stavudine to tenofovir maintained durable virologic suppression when the HAART regimen included a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor, led to a slow improvement of lipoatrophy, and improved the lipid profile and lactate levels with excellent tolerability. These results support the proactive change of stavudine to tenofovir.

Therapeutic Drug Monitoring in the Management of HIV-Infected Patients

The rate of HIV-positive patients that fails to reach or to maintain a durable virological suppression under anti-retroviral (ARV) therapy might be as high as 50%, therefore new tools to improve ARV drug efficacy are urgently needed. Among others, therapeutic drug monitoring (TDM) is a strategy by which the dosing regimen for a patient is guided by measurement of plasma drug levels, enabling physicians to optimize ARV drug efficacy and to avoid drug-related toxicity. The most used analytical methods to determine plasma levels of ARV drugs are HPLC-UV and HPLC-MS(/MS), recently MALDI-based methods and enzyme immunoassay (EIA) technologies have been also employed. The wide inter-patient variability in ARV drug pharmacokinetic supports the application of TDM to the clinical management of HIV-infected patients. Drug-drug and drug-food interactions, drug binding to plasma proteins, drug sequestering by erythrocytes, hepatic impairment, sex, age, pregnancy, and host genetic factors are sources of inter-patient variability affecting ARV drug pharmacokinetics. Combining the information of TDM and resistance tests in genotypic inhibitory quotient (GIQ) is likely to be of great clinical utility. Indeed, only two clinical trials on GIQ, both conducted using ARV drugs not more commonly in use, have shown clinical benefits. The design of new trials with long follow-up and sample size representative of the current HIV prevalence is urgently needed to give indications for GIQ as an early predictor of virological response. Here, the basic principles and the available methods for TDM in the management of HIV-infected patients are reviewed.

Immune restoration during HAART: 8-year follow-up in HIV-positive patients with sustained virological suppression

Purpose of the study Durable virological suppression during HAART is associated with immunological recovery in patients with HIV infection. Current guidelines recommend to initiate HAART when CD4+ cell count falls 350 cells/μl. We retrospectively assessed the long-term immunological outcome in patients with sustained virological suppression during HAART, for up to 8 years.

Pregnancy and HIV Disease Progression during the Era of Highly Active Antiretroviral Therapy

Before the availability of highly active antiretroviral therapy (HAART), there was no clear effect of pregnancy on human immunodeficiency virus (HIV) disease progression. This has not been assessed during the HAART era. We conducted an observational cohort study among HIV-infected women with >or=1 outpatient clinic visit between January 1997 and December 2004. HIV disease progression was defined as the occurrence of an AIDS-defining event or death. Of 759 women who met the inclusion criteria, 139 (18%) had had >1 pregnancy, and 540 (71%) had received HAART. There was no difference in HAART duration by pregnancy status. Eleven pregnant (8%) and 149 nonpregnant (24%) women progressed to AIDS or death. After controlling for age, baseline CD4(+) lymphocyte count, baseline HIV-1 RNA level, and durable virologic suppression in a Cox proportional hazards model that included propensity score for pregnancy, pregnancy was associated with a decreased risk of disease progression (hazard ratio [HR], 0.40 [95% confidence interval {CI}, 0.20-0.79]; P=.009]). In a matched-pair analysis of 81 pregnant women matched to 81 nonpregnant women according to age, baseline CD4(+) lymphocyte count, receipt of HAART, and date of cohort entry, pregnant women had a lower risk of disease progression both before (HR, 0.10 [95% CI, 0.01-0.89]; P=.04) and after (HR, 0.44 [95% CI, 0.19-1.00]; P=.05) the pregnancy event. Pregnancy was associated with a lower risk of HIV disease progression in this HAART-era study. This finding could be the result of the healthier immune status of women who become pregnant or could possibly be related to a beneficial interaction between pregnancy and HAART.

Can treatment interruption strategies improve the management of HIV infection ?

Despite clear success, there is growing appreciation that there are significant limitations with continuous administration of antiretroviral therapy. Currently available treatments are suppressive and cannot eradicate HIV infection. Long-term toxicity may negatively impact quality of life and long-term adherence to anti-HIV therapy and favors emergence of resistant variants. New strategies based on scheduled treatment interruption have been evaluated in various distinct clinical situations with different aims. For patient successfully treated, two major strategies have been proposed : stimulate anti-HIV immune response and reduce drug exposure consisting in off and on treatment periods. For patients with virological failure, stopping antiretroviral therapy during a short period in order to modify the HIV-resistance profile from multidrug resistance to a more sensitive pattern might improve the chances of obtaining durable virological suppression and immunological benefit after resumption of therapy. This review covers the main findings of these investigations and examines the main limitations of scheduled treatment interruptions in terms of clinical progression, emergence of resistance, virus reservoir and risk of viral transmission.

Neurocognitive Impairment and Survival in a Cohort of HIV-Infected Patients Treated with HAART

Before the introduction of HAART, HIV-associated neurocognitive impairment (NCI) was recognized as an independent risk factor for death. Since 1996, we conducted a prospective study to assess whether NCI still represents a negative prognostic factor for mortality. Patients were administered measures of neurocognitive function (a battery of 17 neuropsychological tests), clinical and neurological evaluation, laboratory testing, and brain imaging studies. Among the 412 enrolled patients, 224 (54.4%) were neurocognitively impaired and 188 (45.6%) were neurocognitively unimpaired. A durable virological suppression under highly active antiretroviral therapy (HAART) was achieved by 63.3% of unimpaired patients and by 49.6% of impaired patients (p = 0.007). Overall, 47 deaths were recorded, 38 among impaired and 9 among unimpaired patients. At 84 months, the estimated survival proportions in impaired and unimpaired patients were 68.5% and 84.9%, respectively (p < 0.001). At univariate analysis the virological response to HAART was the variable most strongly associated with survival, since patients with virological failure had a nearly 10-fold increased risk of death than those with durable virological suppression (HR = 9.9, 95% CI: 3.9-25.0). After stratification for virological response to HAART, an increased risk of death for neurocognitively impaired patients was seen only among the 182 patients with virological failure (HR: 2.9, 95% CI: 1.2-7.1), while the survival probability of the 230 patients with durable virological suppression was not affected by neurocognitive impairment (p = 0.89). Our results highlight the clinical relevance of HIV-related central nervous system (CNS) involvement in the HAART era, and raise concerns regarding the clinical relevance of CNS involvement as potent antiretroviral therapies become less effective.

Incomplete HIV Type 1 Antibody Evolution and Seroreversion in Acutely Infected Individuals Treated with Early Antiretroviral Therapy

The diagnosis of human immunodeficiency virus type 1 (HIV-1) infection by standard tests relies on the formation of HIV-1-specific antibodies. Early treatment of acute HIV-1 infection may have unique immunologic effects on host cellular and humoral responses. Rare cases of HIV-1 seroreversion have been reported for patients with advanced or rapidly progressive disease. Here, we report seroreversion that occurred in subjects with acute HIV-1 infection who initiated early antiretroviral therapy. A total of 150 patients with symptomatic acute or early onset HIV-1 infection that was treated with antiretroviral therapy were observed prospectively by means of monthly clinical and laboratory evaluation, which included serial HIV enzyme-linked immunosorbent assay and Western blots, until a fully evolved HIV-1 antibody response was documented. Three patients who initiated antiretroviral therapy a mean interval of 8 days (range, 1-16 days) after presentation and were observed for a mean duration of 50.2 months (range, 40.2-55.7 months) did not develop a fully evolved HIV-1 antibody response or demonstrated complete or partial HIV-1 seroreversion, despite maintenance of cytomegalovirus-specific humoral responses. Virologic suppression and seroreversion (complete or partial) occurred a mean duration of 4.1 months (range, 2.3-5.7 months) and 15.5 months (range, 6.7-26.3 months), respectively, after the initiation of therapy. All patients maintained complete virologic suppression while receiving therapy and had an undetectable HIV-1 RNA load at the time of seroreversion. Early antiretroviral therapy associated with durable virologic suppression in acute HIV-1 infection may abrogate the formation or detection of HIV-1-specific antibodies. Ongoing antigenic stimulation may be required to maintain HIV-1-specific humoral responses. Incomplete evolution of the HIV-1 antibody response and/or presence of seroreversion (although infrequently observed) underscore the potential unique immunologic effect of early antiretroviral therapy in patients with primary HIV-1 infection.

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.

On the basis of studies with relatively short follow-up, treatment guidelines currently recommend that highly active antiretroviral therapy (HAART) be initiated in asymptomatic human immunodeficiency virus-infected patients when the CD4+ lymphocyte count is < or =200 cells/mm3. We assessed the development of a new opportunistic infection or death among 1173 patients initiating HAART. Durable virologic suppression was defined as having more undetectable (<400 copies/mL) than detectable virus loads after the initiation of therapy. The median durations of therapy and follow-up were 29 and 36 months, respectively. Among patients who achieved durable virologic suppression, those with baseline CD4+ lymphocyte counts of <200 cells/mm3 tended to progress faster than those with baseline CD4+ lymphocyte counts of 201-350 cells/mm3 (P=.09) and progressed faster than those with baseline CD4+ lymphocyte counts of >350 cells/mm3 (P=.01). Among those with durable virologic suppression, there was no difference in disease progression between those with baseline CD4+ lymphocyte counts of 201-350 cells/mm3 and those with durable virologic suppression with baseline CD4+ lymphocyte counts of >350 cells/mm3 (P=.40). Initiating HAART with a CD4+ lymphocyte count of <200 cells/mm3 was associated with a higher risk of disease progression, even with durable virologic suppression. HAART should be initiated at CD4+ lymphocyte counts of >200 cells/mm3.

Compact Quadruple Therapy with the Lamivudine/Zidovudine Combination Tablet Plus Abacavir and Efavirenz, Followed by the Lamivudine/Zidovudine/Abacavir Triple Nucleoside Tablet Plus Efavirenz in Treatment-Naïve HIV-Infected Adults

Purpose: To assess efficacy, safety, and adherence with compact quadruple therapy comprising one lamivudine 150-mg/zidovudine 300-mg tablet (COM) twice daily + one abacavir (ABC) 300-mg tablet twice daily + three efavirenz (EFV) 200-mg capsules at bedtime for 24 weeks, followed by one lamivudine 150-mg/zidovudine 300-mg/ABC 300-mg triple nucleoside tablet (TZV) twice daily + three EFV 200-mg capsules at bedtime for 24 weeks. Method: A pilot 48-week, prospective, open-label trial in which 38 antiretroviral-naïve HIV-infected adults (baseline median HIV-1 RNA 5.1 log10 copies/mL, CD4+ cell count 285/μL) received the above treatment and were monitored regularly with respect to plasma HIV-1 RNA levels, CD4+ cell counts, T-cell receptor excision circles (TRECs), adherence, and adverse events. Results: At Week 48, intent-to-treat, switch-included analysis showed plasma HIV-1 RNA levels <400 copies/mL in 100% (29/29) of patients and <50 copies/mL in 93% (27/29); 59% of patients who achieved <50 copies/mL had <3 copies/mL (16/27). Similar virologic suppression was observed in patients with baseline HIV-1 RNA above or below 100,000 copies/mL. HIV-1 RNA and CD4+ cell counts changed from baseline by a median of –3.4 log10 copies/mL and +172 cells/μL, respectively. One virologic failure occurred at Week 16. Median TRECs/100,000 peripheral blood lymphocytes increased 6-fold between baseline and Week 48. Median adherence rates were consistently 100% by self-report and 94% by pill count. Grade 2-4 treatment-related adverse events included dreams (16%), nausea (13%), decreased white cells (8%), dizziness (8%), sleep disorders (8%), and malaise and fatigue (8%). A suspected ABC hypersensitivity reaction occurred in 8% (3/38) of patients. Conclusion: COM/ABC/EFV or TZV/EFV produced potent, durable virologic suppression and immunologic benefits, was associated with high adherence rates, and was generally well tolerated.