Non-nucleoside Reverse Transcriptase Inhibitor-based Regimens Research Articles

Scale-up of national antiretroviral therapy programs: progress and challenges in the Asia Pacific region

There has been tremendous scale-up of antiretroviral therapy (ART) services in the Asia Pacific region, which is home to an estimated 4.7 million persons living with HIV/AIDS. We examined treatment scale-up, ART program practices, and clinical outcome data in the nine low-and-middle-income countries that share over 95% of the HIV burden in the region. Standardized indicators for ART scale-up and treatment outcomes were examined for Cambodia, China, India, Indonesia, Myanmar, Nepal, Papua New Guinea, Thailand, and Vietnam using data submitted by each country to the WHO/The Joint United Nations Programme on HIV/AIDS (UNAIDS)/UNICEF joint framework tool for monitoring the health sector response to HIV/AIDS. Data on ART program practices were abstracted from National HIV Treatment Guidelines for each country. At the end of 2009, over 700,000 HIV-infected persons were receiving ART in the nine focus countries. Treatment coverage varies widely in the region, ranging from 16 to 93%. All nine countries employ a public health approach to ART services and provide a standardized first-line nonnucleoside reverse transcriptase inhibitor-based regimen. Among patients initiated on first-line ART in these countries, 65-88% remain alive and on treatment 12 months later. Over 50% of mortality occurs in the first 6 months of therapy, and losses to follow-up range from 8 to 16% at 2 years. Impressive ART scale-up efforts in the region have resulted in significant improvements in survival among persons receiving therapy. Continued funding support and political commitment will be essential for further expansion of public sector ART services to those in need. To improve treatment outcomes, national programs should focus on earlier identification of persons requiring ART, decentralization of ART services, and the development of stronger healthcare systems to support the provision of a continuum of HIV care.

Association between Detection of HIV‐1 DNA Resistance Mutations by a Sensitive Assay at Initiation of Antiretroviral Therapy and Virologic Failure

Antiretroviral therapy (ART) has become more available throughout the developing world during the past 5 years. The World Health Organization recommends nonnucleoside reverse-transcriptase inhibitor-based regimens as initial ART. However, their efficacy may be compromised by resistance mutations selected by single-dose nevirapine (sdNVP) used to prevent mother-to-child transmission of human immunodeficiency virus (HIV)-1. There is no simple and efficient method to detect such mutations at the initiation of ART. One hundred eighty-one women who were participating in a clinical trial to prevent mother-to-child transmission and who started NVP-ART after they had received sdNVP or a placebo were included in the study. One hundred copies of each patient's HIV-1 DNA were tested for NVP-resistance point-mutations (K103N, Y181C, and G190A) with a sensitive oligonucleotide ligation assay that was able to detect mutants even at low concentrations (> or = 5% of the viral population). Virologic failure was defined as confirmed plasma HIV-1 RNA >50 copies/mL after 6 to 18 months of NVP-ART. At initiation of NVP-ART, resistance mutations were identified in 38 (26%) of 148 participants given sdNVP (K103N in 19 [13%], Y181C in 8 [5%], G190A in 28 [19%], and > or = 2 mutations in 15 [10%]), at a median 9.3 months after receipt of sdNVP. The risk of virologic failure was 0.62 (95% confidence interval [CI], 0.46-0.77) in women with > or = 1% resistance mutation, compared with a risk of 0.25 (95% CI, 0.17-0.35) in those without detectable resistance mutations (P < .001). Failure was independently associated with resistance, an interval of <6 months between sdNVP and NVP-ART initiation, and a viral load higher than the median at NVP-ART initiation. Access to simple and inexpensive assays to detect low concentrations of NVP-resistant HIV-1 DNA before the initiation of ART could help improve the outcome of first-line ART.

The Impact of Transmitted Drug-Resistance on Treatment Selection and Outcome of First-Line Highly Active Antiretroviral Therapy (HAART)

The study aim was to determine how resistance testing influences outcome of first-line highly active antiretroviral therapy (HAART) in routine practice in the United Kingdom. The prevalence of transmitted drug resistance and the genotypic sensitivity score (GSS) of first-line HAART regimens were determined using data from the UK Collaborative HIV Cohort(CHIC) Study. Factors associated with starting a regimen with a reduced GSS and subsequent virological responses were analyzed by logistic and Cox regression. Amongst patients tested in 1999–2006, 116 of 1175 (10%) had $1 resistance mutation; 64 patients (5.4%) had $1 mutation associated with resistance to drugs in the initial HAART regimen and 54 (4.6%) showed a GSS, 3. Factors independently associated with a GSS, 3 were starting HAART in 1999–2001 vs. 2004–2006 (odds ratio = 2.63; 95% confidence interval: 1.19 to 5.83) and use of ritonavir-boosted protease inhibitor (PI/r)–based vs. nonnucleoside reverse transcriptase inhibitor–based regimens (1.97; 1.06 to 3.64). AGSS .3 was independently associated with virological suppression(hazard ratio for GSS, 3 = 0.60; 95% confidence interval 0.41 to 0.87). Most patients starting HAART after undergoing resistance testing received regimens with a GSS $3. PI/r-based therapy was often selected in patients with resistance to the nucleoside reverse transcriptase inhibitor backbone. Low GSS predicted poor virological suppression and the association persisted after adjusting for PI/r use.

Immunological response to highly active antiretroviral therapy following treatment for prevention of mother to child transmission of HIV‐1: a study in Côte d'Ivoire

BackgroundInformation is currently limited on the long-term follow up of HIV-1 infected women who are on highly active antiretroviral therapy (HAART) that contains nevirapine and lamivudine and who were previously exposed to antiretroviral drugs for the prevention of mother to child transmission (PMTCT) of HIV.MethodsWe studied the 36-month immunological response to HAART in HIV-1 infected women in Côte d'Ivoire. The women were previously exposed to antiretroviral drug regimens for PMTCT, including single-dose nevirapine and/or short-course zidovudine with or without lamivudine. All HAART regimens included a non-nucleoside reverse transcriptase inhibitor.ResultsAt 36 months: the median absolute increase in CD4+ T cell count was +359 cells/mm3 (IQR: 210-466) in 200 women who had undergone 36-month follow-up visits; +359 cells/mm3 (IQR: 222-491) in 88 women not exposed to PMTCT antiretrovirals; and +363 cells/mm3 (IQR: 200-464) in 112 women exposed to at least one antiretroviral PMTCT regimen. Overall, 49 (19.8%) of the 247 women who initiated HAART met the immunological failure criteria at least once during follow up. The overall probability of immunological failure was 0.08 (95% CI: 0.12-0.15) at 12 months, and 0.21 (95% CI: 0.16-0.27) at 36 months. No difference was observed according to the presence or absence of resistance mutations to nevirapine or lamivudine in women tested at four weeks postpartum. In addition, at 36 months, 23% of women were lost to follow up, dead or had stopped their treatment.ConclusionsA non-nucleoside reverse transcriptase inhibitor-based antiretroviral regimen, initiated a year or more after PMTCT exposure and that includes nevirapine, remains a good option for at least the first 36 months of treatment.

Antiretroviral Adherence and Pharmacokinetics: Review of Their Roles in Sustained Virologic Suppression

High levels of adherence to antiretrovirals are important to prevent the development of genotypic resistance and achieve virologic suppression. Although the decreased complexity of regimens is associated with improved adherence, there is little evidence that adherence is better with once-daily dosing regimens compared to twice-daily regimens. The relationship between adherence, resistance, and virologic suppression is different for different classes of antiretrovirals. Boosted protease inhibitor (PI)-based regimens are preferred to unboosted PI-based regimens for patients with poor adherence. With PI-based regimens, the pharmacologic consequence of a single missed dose is greater with a once-daily regimen than with a twice-daily regimen (e.g., once-daily versus twice-daily lopinavir/ritonavir). Although resistance is a concern for patients taking non-nucleoside reverse transcriptase inhibitor-based regimens with imperfect adherence, virologic suppression can be achieved with less than 95% adherence. It is important for clinicians to address adherence problems in their patients and to tailor individual regimens based on treatment history, genotype resistance, side effect profile, drug interactions, pharmacokinetics, schedule preferences, and perceived adherence.

Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy

To examine the accuracy of the World Health Organization immunological criteria for virological failure of antiretroviral treatment. Analysis of 10 treatment programmes in Africa and South America that monitor both CD4 cell counts and HIV-1 viral load. Adult patients with at least two CD4 counts and viral load measurements between month 6 and 18 after starting a non-nucleoside reverse transcriptase inhibitor-based regimen were included. WHO immunological criteria include CD4 counts persistently <100 cells/microl, a fall below the baseline CD4 count, or a fall of >50% from the peak value. Virological failure was defined as two measurements > or =10 0000 copies/ml (higher threshold) or > or =500 copies/ml (lower threshold). Measures of accuracy with exact binomial 95% confidence intervals (CI) were calculated. A total of 2009 patients were included. During 1856 person-years of follow up 63 patients met the immunological criteria and 35 patients (higher threshold) and 95 patients (lower threshold) met the virological criteria. Sensitivity [95% confidence interval (CI)] was 17.1% (6.6-33.6%) for the higher and 12.6% (6.7-21.0%) for the lower threshold. Corresponding results for specificity were 97.1% (96.3-97.8%) and 97.3% (96.5-98.0%), for positive predictive value 9.5% (3.6-19.6%) and 19.0% (10.2-30.9%) and for negative predictive value 98.5% (97.9-99.0%) and 95.7% (94.7-96.6%). The positive predictive value of the WHO immunological criteria for virological failure of antiretroviral treatment in resource-limited settings is poor, but the negative predictive value is high. Immunological criteria are more appropriate for ruling out than for ruling in virological failure in resource-limited settings.

Adverse Drug Reactions to Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Regimen: A 24-Week Prospective Study

Few studies have addressed the issue of adverse drug reactions with non-protease inhibitor (PI)-based antiretroviral therapy (ART) in resource-constrained settings. We studied prospectively the incidence of adverse drug reactions with generic ART among our patients. A total of 100 HIV-infected individuals were recruited. Patients received nevirapine (NVP) or efavirenz (EFV) with lamivudine (3TC) and zidovudine (ZDV)/stavudine (d4T). They were followed for 6 months for evidence of adverse drug reactions. The mean CD4 count was 114.09 +/- 60.07 cells/mm(3) (range, 12-232 cells/mm(3)). Transient gastrointestinal symptoms were most frequent. Fourteen individuals (12 receiving ZDV/d4T, 3TC, NVP and 2 receiving ZDV/d4T, 3TC, EFV) developed skin rash. Among patients receiving NVP, 25.7% developed grade 1 hepatotoxicity. Three patients had numbness in both lower limbs. Among those individuals who received EFV, 32.3% individuals had central nervous system (CNS) symptoms in the form of insomnia, vivid dreams, dizziness, and drowsiness. As the developing world increasingly uses generic ART, the clinician must be constantly vigilant for treatment-related adverse events.

Tolerability and Efficacy of PI Versus NNRTI-Based Regimens in Subjects Receiving HAART During Acute or Early HIV Infection

Little is known about modifications to highly active antiretroviral therapy (HAART) initiated during acute or early HIV infection. Reasons for first modifications of HAART regimens were recorded using the AIDS Clinical Trials Group form among 363 subjects who initiated HAART within 1 year of seroconversion from 2005 in the Acute Infection and Early Disease Research Program. Modifications recorded as due to "patient choice" or "physician choice" were clarified by query to the recording site. Times to events were analyzed by Kaplan-Meier methods; significance of differences was assessed by the log-rank test. Two hundred five of 363 (56%) subjects modified therapy, at a median of 425 days after initiation, by changing drugs, discontinuing treatment, or removing or adding drugs. Most modifications were attributed to toxicity (n = 105, 51%), most of which was low grade; regimen simplification (n = 18, 5%); and achievement of viral suppression (n = 15, 7%). Time to first modification was shorter for those with shorter time from infection to initiation (P = 0.005) and those having higher CD4 lymphocyte count at initiation (P = 0.06). Modifications occurred sooner in subjects receiving regimens taken more than once daily (P < 0.001) or with more than 2 pills daily (P < 0.001). Most regimens were nonnucleoside reverse transcriptase inhibitor based or protease inhibitor based, and these did not differ significantly in rate and timing of modification. HAART initiated early in HIV infection was modified in the majority of cases, usually due to minor toxicities whose incidence was similar for protease inhibitor-based and nonnucleoside reverse transcriptase inhibitor-based regimens. Convenience of regimens (lower pill burden and dosing frequency) was associated with a lower rate of modification.

Markov modelling of HIV infection evolution in the HAART era

The aim was to investigate the impact of the main prognostic factors on HIV evolution. A multi-state Markov model was applied in a cohort of 2126 patients to estimate impact of these factors on patients' clinical and immunological evolutions. Clinical progression and immunological deterioration shared most of their prognostic factors: male gender, intravenous drug use, weight loss, low haemoglobin level (<110 g/l), CD8 cell count (<500/mm(3)) and HIV viral load (>5 log(10) copies/ml). Highly active retroviral therapy reduced the risks of clinical progression and immune deterioration whatever patients' CD4 cell count. Risk reductions were 41-60% for protease inhibitor-based and 27-68% for non-nucleoside reverse transcriptase inhibitor-based regimens. Three-year transition probabilities showed that only patients with a CD4 cell count >or=350 CD4/mm(3) could in most cases maintain their immunity. This model provides 'real life' transition probabilities from one immunological stage to another, allowing decision analyses that could help determine the beneficial therapeutic strategies for HIV-infected patients.

Virological Suppression Achieved with Suboptimal Adherence Levels among South African Children Receiving Boosted Protease Inhibitor–Based Antiretroviral Therapy

Sixty-six children who were receiving antiretroviral treatment were assessed for treatment adherence and virological outcome to compare boosted protease inhibitor-based regimens with nonnucleoside reverse-transcriptase inhibitor-based regimens. Children who were receiving protease inhibitor-based regimens demonstrated higher rates of virological suppression, even with poor treatment adherence (<80%). In children, boosted protease inhibitors seem to be more forgiving of poor adherence than do nonnucleoside reverse-transcriptase inhibitors.

Clinical and immunological outcomes of a national paediatric cohort receiving combination antiretroviral therapy in Uganda

We aimed to evaluate clinical and immunological outcomes of paediatric patients receiving combination antiretroviral therapy (cART) enrolled in The AIDS Support Organization (TASO) Uganda national HIV/AIDS programme. Observational study of patients (age <14 years) enrolled in 10 clinics across Uganda for which TASO has data. We extracted patient demographic, immunological and clinical outcomes from the TASO databases regarding age, sex, cART regimen, CD4 cell count and WHO stage at initiation, tuberculosis, mortality and adherence. Outcomes were analysed using Pearson's rank-order correlations, Wilcoxon's rank sum tests, Cox proportional hazard model and survivor functions. Of the total 770 HIV children on cART, median age was 9 years (interquartile range, 5-13 years), and median follow-up time was 377 days (interquartile range, 173-624 days). Seven hundred and fifty-one children (97.5%) initiated nonnucleoside reverse transcriptase inhibitor-based regimens. Three hundred and sixty-five children (47.5%) initiated cART with severe immune suppression (CD4 cell percentage <15). Of the 18 (2.3%) children that died, mortality was associated with lower CD4 cell percentage at initiation (B coefficient -0.144, standard error 0.06, P = 0.02). Of the total, 229 (30%) were single or double orphans and more likely to initiate cART at an older age (mean age, 9.25 vs. 8.35 years, P = 0.02) and have a lower CD4 cell count (median, 268 vs. 422 cells/microl, P < or = 0.0001) and CD4 cell percentage (median 12.8 vs. 15.5%, P = 0.02) at initiation. Pulmonary tuberculosis was present in 43 (5.6%) patients at initiation and 21 (2.3%) after cART. Almost all patients (94.9%) demonstrated more than 95% adherence. Children on cART in Uganda demonstrate positive clinical outcomes. However, additional support is required to ensure timely cART access among orphans and young children.

Viral resuppression and detection of drug resistance following interruption of a suppressive non-nucleoside reverse transcriptase inhibitor-based regimen

Interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance. Limited data exist to guide clinical practice on the best interruption strategy to use. Patients in the drug-conservation arm of the Strategies for Management of Antiretroviral Therapy (SMART) trial who interrupted a fully suppressive NNRTI-regimen were evaluated. From 2003, SMART recommended interruption of an NNRTI by a staggered interruption, in which the NNRTI was stopped before the NRTIs, or by replacing the NNRTI with another drug before interruption. Simultaneous interruption of all antiretrovirals was discouraged. Resuppression rates 4-8 months after reinitiating NNRTI-therapy were assessed, as was the detection of drug-resistance mutations within 2 months of the treatment interruption in a subset (N = 141). Overall, 601/688 (87.4%) patients who restarted an NNRTI achieved viral resuppression. The adjusted odds ratio (95% confidence interval) for achieving resuppression was 1.94 (1.02-3.69) for patients with a staggered interruption and 3.64 (1.37-9.64) for those with a switched interruption compared with patients with a simultaneous interruption. At least one NNRTI-mutation was detected in the virus of 16.4% patients with simultaneous interruption, 12.5% patients with staggered interruption and 4.2% patients with switched interruption. Fewer patients with detectable mutations (i.e. 69.2%) achieved HIV-RNA of 400 copies/ml or less compared with those in whom no mutations were detected (i.e. 86.7%; P = 0.05). In patients who interrupt a suppressive NNRTI-regimen, the choice of interruption strategy may influence resuppression rates when restarting a similar regimen. NNRTI drug-resistance mutations were observed in a relatively high proportion of patients. These data provide additional support for a staggered or switched interruption strategy for NNRTI drugs.

Protease inhibitor therapy in resource-limited settings

The use of protease inhibitors in resource-limited settings will increase in coming years as HIV treatment cohorts mature. We review data available to guide the expanded use of protease inhibitors in these settings. The safety and effectiveness of protease inhibitors may be affected by the context of their use, yet limited data exist regarding the use of these agents in resource-limited settings in either first or subsequent regimens. Critically, data are needed regarding optimal regimens at time of first-line nonnucleoside reverse transcriptase inhibitor-based regimen failure. A number of alternative strategies are being investigated, including dual-boosting, monotherapy and dose reduction. Despite recent progress cost, storage requirements, drug interactions and formulation continue to hinder the use of protease inhibitors, particularly for children. Protease inhibitors are the core component of second-line therapy in resource-limited settings and are used in specific situations in first-line therapy. Use of second-line regimens has been more diverse than first line, but WHO has recently prioritized regimens containing lopinavir/ritonavir or ritonavir-boosted atazanavir. As use of protease inhibitors in resource-limited settings increases evidence needs to be accrued to guide further expanded use.

Increased regimen durability in the era of once-daily fixed-dose combination antiretroviral therapy

Data on initial antiretroviral regimen longevity predates the arrival of newer nucleoside reverse transcriptase inhibitor backbones and once-daily regimens. Modern regimens are thought to possess greater tolerability and convenience. We hypothesized this would translate into greater durability. Retrospective study of antiretroviral-naive patients starting treatment at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic 1 January 2000-31 July 2007. Two periods of antiretroviral initiation were identified, prior and after August 2004 (arrival of once-daily fixed-dose regimens). Kaplan-Meier survival analyses of regimen durability by time period and regimen characteristics were performed. Staged Cox proportional hazards models evaluated the roles of dosing complexity and composition in explaining differences in regimen durability between study periods. Overall 542 patients started antiretroviral drugs (n = 309, January 2000-July 2004; n = 233, August 2004-July 2007). Median durability was 263 days longer in after August 2004 regimens. Regimens started before August 2004 had increased hazards for discontinuation relative to after August 2004 regimens [hazard ratio (HR) = 1.44; 95% confidence interval (CI) = 1.03-2.02]. Time period of initiation lost statistical significance when the model included dosing frequency (HR = 1.92 for at least twice daily vs. daily; 95% CI = 1.29-2.88). As regimen composition variables were added, time period and dosing frequency lost significance. Increased hazards of discontinuation were observed with didanosine or stavudine relative to abacavir or tenofovir use (HR = 1.92; 95% CI = 1.29-2.88) and all third drugs compared with non-nucleoside reverse transcriptase inhibitor-based regimens (triple-nucleoside reverse transcriptase inhibitor HR = 1.76; 95% CI = 1.14-2.73; unboosted-protease inhibitor HR = 1.58; 95% CI = 1.02-2.46; boosted-protease inhibitor HR = 1.57; 95% CI = 1.02-2.41). Affective mental health disorders increased the hazard of discontinuation in all models. Durability of contemporary once-daily fixed-dose antiretroviral regimens has significantly eclipsed the duration of earlier antiretroviral drug options. Our results indicate this is due to both more convenient dosing and improved tolerability of modern antiretroviral regimens.

Clinical impact of patient population differences and genomic variation in efavirenz therapy

Guidelines for use of antiretroviral agents presently recommend first-line treatments with nonnucleoside reverse transcriptase inhibitor-based regimens. Efavirenz is the standard-of-care comparator for nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy. As with many antiretroviral medications, efavirenz is subject to interindividual variation in metabolism, effectiveness, and tolerability. Demographic factors such as age, sex, and ethnicity have been demonstrated to influence this variability, but other underlying factors such as genetics, disease state, and concomitant drug use can also play a role. The clinical impactions of these factors are only beginning to be understood. Although significant advances have led to a greater understanding of interactions between genetic and host factors that influence the efficacy and toxicity of efavirenz, providers should not withhold treatment of HIV infection with an efavirenz-based regimen on the basis of racial or ethic categorizations.

Evaluating Adherence to Highly Active Antiretroviral Therapy with Use of Pill Counts and Viral Load Measurement in the Drug Resources Enhancement against AIDS and Malnutrition Program in Mozambique

Maintaining treatment adherence among the growing number of patients receiving antiretroviral treatment in Africa is a dramatic challenge. The objective of our study was to explore the results of a computerized pill count method and to test the validity, sensitivity, and specificity of this method with respect to viral load measurement in an African setting. We performed a prospective, observational study involving patients who received first-line highly active antiretroviral therapy in Mozambique from 1 April 2005 through 31 March 2006. Enrolled patients had received treatment for at least 3 months before the study. For defining treatment adherence levels, pill counts were used, and the results were analyzed with viral load measurements at the end of the observation period. The study involved 531 participants. During the 12 months of observation, 137 patients left the program or discontinued first-line therapy. Of the remaining 394 patients, 284 (72.1%) had >95% treatment adherence; of those 284 patients, 274 (96.5%) had a final viral load <1000 copies/mL. A Cox proportional hazards analysis revealed that the relationship between >95% treatment adherence and the final viral load was closer than that between >90% treatment adherence and viral load. Treatment adherence >95% maximizes the results of the nonnucleoside reverse-transcriptase inhibitor-based regimen. The pill count method appears to be a reliable and economic tool for monitoring treatment adherence in resource-limited settings.

Persistent Intrathecal Immune Activation in HIV-1-Infected Individuals on Antiretroviral Therapy

Neopterin is a well-established marker of macrophage activation. The cerebrospinal fluid (CSF) neopterin levels are elevated in most HIV-1-infected individuals and decrease significantly after initiation of antiretroviral therapy (ART). Unexpectedly, CSF concentrations often remain mildly abnormal even in patients treated for a long time with suppressive ART. The aims of this study were to analyze if persistently elevated CSF neopterin levels were associated with the type of antiretroviral regimen or with low-level CSF HIV-1 concentrations and to evaluate if plasma HIV-1 RNA levels correlated to lingering CSF neopterin concentrations in patients with effective ART. One hundred fifty-seven chronically HIV-1-infected patients with stable ART for > or =6 months and no neurologic symptoms were included, and 193 HIV-1-infected patients without ART served as controls. Neopterin was analyzed with a radioimmunoassay or an enzyme-linked immunosorbent assay. HIV-1 RNA quantification was performed with the Roche Amplicor assay (version 1.5; Hoffman-La Roche, Basel, Switzerland). Two quantitative HIV-1 RNA assays with sensitivities < or =2.5 copies/mL were used in 40 samples. As anticipated, HIV-1 RNA and CSF neopterin levels were markedly lower in patients on ART compared with untreated controls. No significant difference in CSF neopterin concentrations was found between those treated with protease inhibitor- and nonnucleoside reverse transcriptase inhibitor-based regimens in combination with 2 nucleoside analogues. Subjects with CSF HIV-1 RNA loads <2.5 copies/mL had the lowest CSF neopterin levels. Plasma viral load had no impact on intrathecal immune activation in cases with CSF viral loads <50 copies/mL. The persistent intrathecal cell-mediated immune response was associated with CSF viral load but not with treatment regimen in individuals on ART.

Optimal Timing and Best Antiretroviral Regimen in Treatment-naive HIV-Infected Individuals with Advanced Disease

The introduction of highly active antiretroviral therapy (HAART) in developed countries has achieved a good control of HIV infection. Despite this, a delayed HIV diagnosis makes it necessary to start antiretroviral treatment in individuals with severe impairment of their immunological function. Very often, this is accompanied by an opportunistic infection that needs to be treated, with a consequent complication of management because of overlapping toxicities and pharmacokinetic interactions with antiretroviral drugs, and a greater pill burden. All this could impair adherence and reconstitution of the immune function with a paradoxical clinical worsening in some patients, especially if the CD4 cell count is below 50 cells/microl. The best antiretroviral regimen and the best timing for starting antiretroviral therapy in treatment-naive patients with advanced infection have not yet been established. Recommendations for the clinical management of advanced HIV disease come from panels of experts in the therapy of opportunistic infections and antiretroviral treatment, and they advise starting combined antiretroviral therapy 2-4 weeks after initiating treatment of the opportunistic infection. Many patients have been successfully treated with a pharmacologically enhanced (boosted) protease inhibitor (mainly lopinavir/ritonavir)-based regimens. The efficacy of non-nucleoside reverse transcriptase inhibitor-based regimens for the treatment of very immunosuppressed patients has been tested in few clinical trials during the HAART era. Some cohort studies and randomized clinical trials support the use of efavirenz-based antiretroviral therapy for the treatment of advanced HIV-1-infected patients; however, recent randomized controlled data suggest, in a moderately advanced HIV population, a better CD4 cell recovery for lopinavir-ritonavir than for efavirenz-treated patients, but a greater virological suppression in the efavirenz arm. Further randomized clinical trials are needed in order to determine whether the efficacy, tolerability and the immunological reconstitution of efavirenz-based therapy can match that achieved with lopinavir/ritonavir or other current boosted protease inhibitor regimens in advanced patients.

Timing of Cryptococcal Immune Reconstitution Inflammatory Syndrome After Antiretroviral Therapy in Patients With AIDS and Cryptococcal Meningitis

Cryptococcosis is the most common lethal fungal infection in patients with AIDS. The introduction of combined antiretroviral therapy (ART) has markedly decreased the overall mortality for these advanced HIV-infected patients. After initiation of ART some patients experience immune reconstitution inflammatory syndrome (IRIS) a well-recognized complication of ART in patients with extremely low initial CD4 cell counts. This syndrome has been described in multiple opportunistic pathogens commonly with Mycobacterium avium complex Mycobacterium tuberculosis Cryptococcus neoformans cytomegalovirus and hepatitis virus. Various studies reported that 8% to 50% of patients with cryptococcal infection who responded to ART developed cryptococcal IRIS despite the use of fluconazole therapy. Lortholarya et al have demonstrated that independent risk factors for the occurrence of cryptococcal IRIS are HIV infection that was revealed by cryptococcosis low CD4 cell count fungemia at baseline and initiationof treatment within 2 months of cryptococcosis. In noncryptococcal IRIS most patients present in the first 8 weeks after the start of ART. There is little information regarding timing of cryptococcal IRIS however. Previous small studies have described that cryptococcal IRIS can occur from as short as < 2 weeks to 22 months after initiation of ART. (excerpt)

Protease Inhibitor-Based Regimens for HIV Therapy

Antiretroviral (ARV) treatment strategies for HIV-infected patients continue to evolve. Over the past few years, there was a shift towards the use of nonnucleoside reverse transcriptase inhibitor-based regimens, mostly because of better tolerability, a lower pill burden, and improved adherence relative to using protease inhibitor (PI)-based regimens. Although the 2 strategies do afford similar potency and durability, the PI-based regimens provide a higher genetic barrier to the development of ARV resistance. This has become progressively more important for reasons that include increasing rates of baseline ARV resistance in newly infected patients and the risk of developing ARV resistance in treated populations with suboptimal adherence. With the introduction of novel ARVs and reformulated agents with more convenient dosing requirements, improved tolerability, and unique resistance characteristics, boosted PI-based strategies are increasingly being considered when initiating therapy in ARV-naive patients. In this article, the evidence for the use of boosted PIs as early therapy is reviewed, with emphasis on data available from comparative randomized controlled trials.