Geographic and Population Distributions of Human Immunodeficiency Virus (HIV)-1 and HIV-2 Circulating Subtypes: A Systematic Literature Review and Meta-analysis (2010-2021).

BACKGROUND: HIV poses significant challenges for vaccine development due to its high genetic mutation and recombination rates. Understanding the distribution of HIV subtypes (clades) across regions and populations is crucial. In this study, a systematic review of the past decade was conducted to characterize HIV-1/HIV-2 subtypes. METHODS: A comprehensive search was performed in PubMed, EMBASE, and CABI Global Health, yielding 454 studies from 91 countries. RESULTS: Globally, circulating recombinant forms (CRFs)/unique recombinant forms (URFs) accounted for 29% of HIV-1 strains, followed by subtype C (23%) and subtype A (17%). Among studies reporting subtype breakdowns in key populations, 62% of HIV infections among men who have sex with men (MSM) and 38% among people who inject drugs (PWIDs) were CRF/URFs. Latin America and the Caribbean exhibited a 25% increase in other CRFs (excluding CRF01_AE or CRF02_AG) prevalence between 2010-2015 and 2016-2021. CONCLUSIONS: This review underscores the global distribution of HIV subtypes, with an increasing prevalence of CRFs and a lower prevalence of subtype C. Data on HIV-2 were limited. Understanding subtype diversity is crucial for vaccine development, which need to elicit immune responses capable of targeting various subtypes. Further research is needed to enhance our knowledge and address the challenges posed by HIV subtype diversity.

A meta-analysis comparing 48-week treatment outcomes of single and multi-tablet antiretroviral regimens for the treatment of people living with HIV.

OBJECTIVES: To compare outcomes with single tablet regimens (STR) versus multi-tablet regimens (MTR) for human immunodeficiency virus (HIV) treatment using published data. DESIGN: Systematic review and random-effects meta-analysis of literature on approved and investigational HIV regimens. METHODS: The research followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Single or un-blinded studies reporting a direct comparison between STR and MTR were eligible for the meta-analysis. Double-blinded studies were excluded due to lack of difference in pill burden between cohorts. The key outcomes of interest included: adherence rates/proportion meeting target, efficacy, safety/tolerability, non-clinical and economic outcomes. RESULTS: After screening 63 full-text articles and posters, 14 studies were eligible for the meta-analysis. The analysis showed that patients taking STR had improved outcomes over those taking MTR. Patients were significantly more adherent regardless of daily dosing frequency (odds ratio [OR]: 1.96, p < 0.001) and were more likely to achieve virological suppression (relative risk [RR]: 1.05, p = 0.002). There was a trend toward a lower discontinuation risk in the STR cohort, together with reported higher therapy satisfaction, better symptom control, improved health status, reduced healthcare resource utilization and demonstrated cost-effectiveness compared to MTR. There were no differences in CD4 cell count increase (at 48 weeks) or safety outcomes. CONCLUSIONS: The findings of this study confirm previously reported preliminary findings of the advantages of STR over MTR for HIV treatment in adherence, therapy continuation, viral suppression, tolerability, quality of life improvement, cost-effectiveness and healthcare resource utilization.

Is there a higher risk of CNS adverse events for PI monotherapy versus triple therapy? A review of results from randomized clinical trials.

BACKGROUND: Protease inhibitor (PI) monotherapy for treatment could avoid the adverse events, drug resistance, and additional costs associated with other antiretrovirals that are normally used, particularly the nucleoside analogues. PI monotherapy has mainly been compared with standard triple therapy in randomized clinical trials of patients who have HIV RNA suppression at screening and no history of virological failure. METHODS: This review included 11 randomized clinical trials of darunavir/ritonavir (DRV/r) or lopinavir/ritonavir (LPV/r) monotherapy versus triple therapy in 1,267 patients with HIV RNA suppression at baseline who were studied between 48 and 144 weeks. RESULTS: There was no clear difference in the risk of central nervous system (CNS) adverse events between PI monotherapy (either DRV/r or LPV/r) and standard triple drug treatment. There were 2 clinical trials - MONOI (DRV/r) and MOST (LPV/r) - that showed CNS symptoms and detectable HIV RNA levels in the cerebrospinal fluid in a small number of individuals taking PI monotherapy. CONCLUSIONS: There was no consistent evidence from the randomized trials currently available for an additional risk of HIV CNS disease during monotherapy with either LPV/r or DRV/r versus standard triple drug therapy. However, the information on CNS adverse events has not been reported using standardized definitions in the studies. In addition, few randomized studies included detailed analysis of neurocognitive function or detection of HIV RNA in the cerebrospinal fluid.

Dynamics of cellular HIV-1 DNA levels over 144 weeks of darunavir/ritonavir monotherapy versus triple therapy in the MONET trial.

BACKGROUND: In patients receiving combination antiretroviral therapy (ART), switching to monotherapy with ritonavir-boosted darunavir (DRV/r) can maintain plasma HIV-1 RNA suppression with no treatment-emergent drug resistance; effects on cellular HIV-1 DNA burden are less well characterized. METHODS: In MONET, patients on stable combination ART for at least 6 months with plasma HIV-1 RNA <50 copies/mL and no history of virologic failure switched to DRV/r 800/100 mg once daily, either alone (n = 127) or with 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) (n = 129). In a representative subset of 146 patients, total HIV-1 DNA load in peripheral blood mononuclear cells (PBMC) was tested retrospectively at baseline, week 48, week 96, and week 144. RESULTS: Mean HIV-1 DNA levels at baseline vs week 144 were 2.50 vs 2.49 log10 copies/106 PBMC in the monotherapy arm and 2.59 vs 2.61 log10 copies/106 PBMC in the triple therapy arm, with mean (median) changes of -0.05 (-0.03) and +0.03 (+0.01) log10 copies/106 PBMC in the 2 arms, respectively. Overall baseline HIV-1 DNA levels were higher in patients with nadir CD4 counts <200 cell/µL (P<.05) and in patients who over 144 weeks experienced at least 1 HIV-1 RNA measurement >50 copies/mL (P < .05). CONCLUSIONS: In this substudy of the MONET trial, HIV-1 DNA levels remained stable during 144 weeks of either DRV/r monotherapy or triple therapy with DRV/r + 2 NRTIs. In both treatment arms, baseline HIV-1 DNA levels were predicted by the nadir CD4 cell count and predictive of plasma HIV-1 RNA detection during follow-up.

96 week results from the MONET trial: a randomized comparison of darunavir/ritonavir with versus without nucleoside analogues, for patients with HIV RNA <50 copies/mL at baseline.

BACKGROUND: In virologically suppressed patients, switching to darunavir/ritonavir monotherapy could avoid resistance and adverse events from continuing nucleoside analogues. METHODS: Two hundred and fifty-six patients with HIV RNA <50 copies/mL on current antiretrovirals were switched to darunavir/ritonavir 800/100 mg once daily, either as monotherapy (n = 127) or with two nucleoside analogues (n = 129). Treatment failure was defined as two consecutive HIV RNA levels at least 50 copies/mL by week 96, or discontinuation of study drugs. The trial had 80% power to show non-inferiority (δ = -12%) at week 48. Results Patients were 81% male, 91% Caucasian, and had a median baseline CD4 count of 575 cells/mm(3). There were more patients with hepatitis C co-infection at baseline in the monotherapy arm (18%) compared with the triple therapy arm (12%). In the efficacy analysis, HIV RNA <50 copies/mL by week 96 (per protocol, time to loss of virological response, switch equals failure) was 78% versus 82% in the monotherapy and triple therapy arms [difference -4.2%, 95% confidence interval (CI) -14.3% to +5.8%]; in a switch included analysis, HIV RNA <50 copies/mL was 93% versus 92% (difference +1.6%, 95% CI -5.0% to +8.1%). The percentage of patients with HIV RNA <5 copies/mL (optical density from the sample equal to the negative control) remained constant over time in both treatment arms. Conclusions In the week 96 analysis of the MONotherapy in Europe with TMC114 (MONET) trial, switching to darunavir/ritonavir monotherapy showed non-inferior efficacy to darunavir/ritonavir plus two nucleoside analogues in the switch included and observed failure analyses, but not in the main switch equals failure analysis.

Neuropsychiatric adverse events with ritonavir-boosted darunavir monotherapy in HIV-infected individuals: a randomised prospective study.

BACKGROUND: Protease inhibitor monotherapy is an attractive treatment option for HIV-infected subjects. Data assessing neuropsychiatric events with the use of protease inhibitor monotherapy are sparse. METHODS: Clinician- and patient-reported neuropsychiatric events were assessed over 48 weeks in HIV-infected subjects on stable antiretroviral therapy, with a plasma HIV RNA <50 copies/mL, randomised to commence on a one to one basis darunavir/ritonavir (800/100 mg once daily) alone (DRVrMono) or with nucleoside analogues (DRVrNRTI). Patient-reported events were assessed by the Functional Assessment of HIV Infection (FAHI) questionnaire and included an assessment of cognitive function. RESULTS: Of 256 subjects enrolled, clinician-reported grade 1-4 adverse events of the nervous system (all cause) were seen in 16% of patients in each treatment arm. FAHI questionnaires were completed by 206 subjects at 48 weeks. No differences in cognitive functioning or other FAHI scores were observed between study treatment groups: Cognitive Functioning score [mean (SD)] 8.9 (2.4) and 9.0 (2.6) in DRVrMono arm and 8.8 (2.6) and 8.9 (2.8) in DRVrNRTI arm at baseline and week 48, respectively (P value for difference = .76). CONCLUSION: In this exploratory analysis, no differences in the evolution of neuropsychiatric adverse events over 48 weeks are observed in HIV-infected subjects randomised to switch antiretroviral therapy to darunavir/ritonavir with or without nucleoside reverse transcriptase inhibitors.

Evaluation of Cardiovascular Disease Risk in HIV-1-Infected Patients Treated with Darunavir.

INTRODUCTION: We evaluated cardiovascular disease (CVD) risk associated with darunavir treatment and examined the demographic/clinical characteristics of darunavir users based on data from Janssen-sponsored clinical trials, post-marketing pharmacovigilance databases, and administrative claims databases. METHODS: First, selected CVD events [myocardial infarction, stroke, sudden death, invasive cardiovascular procedures (coronary artery angioplasty or bypass, or carotid endarterectomy)] were analyzed in 19 Janssen-sponsored phase 2-4 studies (incidence rates estimated from pooled data; 95% confidence intervals derived from Poisson distribution). Second, analyses were conducted to identify spontaneously reported CVD events in post-marketing pharmacovigilance databases and evaluate disproportional reporting of CVD events for darunavir (using Empirical Bayesian Geometric Mean scores). Third, baseline demographic/clinical characteristics of human immunodeficiency virus-1 (HIV-1)-infected patients in general and new users of darunavir and atazanavir were explored using three US administrative claims databases. RESULTS: Among 19 Janssen-sponsored clinical trials (treatment durations ≤ 6 years), the CVD event rate (95% CI) per 1000 person-years (pooled population; n = 5713) was 6.15 (2.91-11.89), and was lower for patients who used once-daily darunavir/ritonavir 800/100 mg [0.71 (0.16-3.05); n = 1326] versus twice-daily darunavir/ritonavir 600/100 mg [9.21 (4.94-16.04); n = 3058]. Trend analysis of post-marketing pharmacovigilance data showed that cumulative CVD event reporting rates for darunavir users (any dose) generally declined over time. Spontaneously reported CVD events were not disproportionately reported with darunavir versus other protease inhibitors. Compared with the general HIV-1-infected population and atazanavir users, higher proportions of darunavir users were male, older, and had comorbidities associated with CVD risk based on results from US administrative claims databases. CONCLUSIONS: This comprehensive review of Janssen-sponsored clinical trial, post-marketing, and epidemiological data does not suggest that CVD should be considered an important risk for users of darunavir.

Correction to: Evaluation of Cardiovascular Disease Risk in HIV­1-Infected Patients Treated with Darunavir.

In the original publication of the article, Table 2 has been published incorrectly.

Pharmacokinetics and Safety of Darunavir/Ritonavir in HIV-Infected Pregnant Women.

The dosage of darunavir/ritonavir is 800/100 mg once daily for treatment-naive patients or treatment-experienced patients with no prior darunavir resistance associated mutations, and 600/100 mg twice daily for treatment-experienced patients with one or more darunavir resistance associated mutations. Results from the five available pharmacokinetic studies show reductions in total darunavir plasma concentrations of between 20-50% during the third trimester of pregnancy. The unbound darunavir concentrations have been measured only in subsets of patients in two of the five pharmacokinetic studies. The unbound concentrations were 11% higher during pregnancy in one study of the 600/100 mg twice-daily dosage, and 13-38% lower during pregnancy for the 800/100 mg once-daily dosage. Ratios of darunavir concentration in cord blood compared to maternal plasma are in the range of 0.11-0.18, suggesting that darunavir does not have high trans-placental penetration. Despite the decrease in exposure, the darunavir/ritonavir 800/100 mg once-daily regimen in HIV-positive pregnant women in combination with background antiretroviral therapy has been effective in preventing mother-to-child transmission in the studies included in this review. Among the 137 infants born across the five studies, there was one case of mother-to-child transmission, which was in a mother taking the 600/100 mg twice-daily dose but who had documented poor adherence to treatment.

Systematic review to determine the prevalence of transmitted drug resistance mutations to rilpivirine in HIV-infected treatment-naive persons.

BACKGROUND: Transmitted drug resistance to antiretrovirals in HIV-1-infected individuals is rising in some regions and could compromise the effectiveness of first-line treatment. It is important to understand the prevalence of resistance to rilpivirine to inform treatment provision. METHODS: A PUBMED/EMBASE search identified analyses of transmitted genotypic resistance to specific non-nucleoside reverse transcriptase inhibitor mutations worldwide. Patients were to be HIV-1-infected and antiretroviral-naive. Rilpivirine mutations assessed were: L100I, K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C and M230I/L. Additionally, frequency of resistance mutations were extracted and pooled by HIV subtype from the Stanford HIV drug resistance database. RESULTS: 138 eligible articles from 65 countries were identified (n=64,466). Among these 64,466 samples, 7 of the 9 genotypic rilpivirine mutations had a prevalence <0.1%. Two mutations were more prevalent: E138A/G/K/Q/R (0.7%, 95% CI 0.2, 1.3) and Y181C/I/V (0.3%, 95% CI 0.2, 0.4). Prevalence of E138 rilpivirine-related mutations varied between regions: highest in Latin America/Caribbean (3.6%, 95% CI 1.0, 7.6) and in Europe (3.2%, 95% CI 0.7, 6.9). Pooled results from the Stanford database (n=52,680) correlated with these findings indicating a low prevalence of 8/9 rilpivirine mutations (<0.1%), except for E138A/G/K/Q/R (2.9%, 95% CI 1.8, 4.4). Prevalence of the mutations at E138 varied significantly by HIV subtype and was highest for subtype-C (6.1%), subtype-F (5.1%) and subtype-A (3.3%). CONCLUSIONS: The prevalence of most transmitted rilpivirine-related HIV mutations is generally low in treatment-naive HIV-1-infected individuals (<0.1%). The prevalence of E138A/G/K/Q/R mutations is higher (0.7%) and varies according to geographical region and HIV subtype.

When can HIV clinical trials detect treatment effects on drug resistance?

Methods of sampling patients for resistance testing, and statistical analyses of HIV drug resistance, have not been standardised in HIV clinical trials. We analysed methods of genotyping and rates of treatment-emergent drug resistance from 27 clinical trials identified from a MEDLINE search. Sample size calculations were conducted using NQUERY software, assuming 5% significance level, 80% power and 1:1 randomisation. The percentage of patients with treatment-emergent IAS-USA mutations after 96 weeks ranged from 1.8% to 9.1% for first-line 2NRTI/NNRTI treatments, 0.6% to 6.3% for first-line 2NRTI/PI/r treatments and 0.0% to 2.0% in switch trials of boosted PIs. The prevalence of drug resistance was higher in trials with no screening for drug resistance at baseline, where the HIV RNA cut-off for genotyping was >50 copies/mL, where patients were tested for drug resistance after discontinuation of treatment, and where follow-up times were 96 weeks or longer. HIV clinical trials could be designed to detect differences in the risk of HIV drug resistance between treatments, as an analysis supporting HIV RNA suppression as the primary endpoint. However, this would require a standardised approach, with intent-to-treat analyses, testing of all samples with HIV RNA>50 copies/mL and genotyping after drug discontinuation.

Week 48 efficacy and central nervous system analysis of darunavir/ritonavir monotherapy versus darunavir/ritonavir with two nucleoside analogues.

BACKGROUND: In previous studies in virologically suppressed patients, protease inhibitor monotherapy has shown trends for more low-level elevations in HIV-1 RNA compared with triple therapy, but no increase in the risk of drug resistance. METHODS: A total of 273 patients with HIV-1 RNA less than 50 copies/ml on first-line antiretrovirals switched to darunavir/ritonavir (DRV/r) 800/100 mg once daily, either as monotherapy (n = 137) or as triple therapy with two nucleoside analogues (n = 136). Treatment failure was defined as HIV-1 RNA levels 50 copies/ml or above, or discontinuation of study treatment by week 48 (FDA Snapshot algorithm). RESULTS: Patients were 83% male and 88% white, with mean age 42 years. In the primary efficacy analysis, HIV-1 RNA less than 50 copies/ml by week 48 [intention-to-treat (ITT)] was 118 of 137 (86%) in the DRV/r monotherapy arm versus 129 of 136 (95%) in the triple therapy arm (difference = -8.7%, 95% confidence interval -15.50, -1.80). In a post-hoc analysis, for patients with nadir CD4 cell count 200 cells/µl or above, rates of HIV-1 RNA suppression were 91 of 96 (95%) in the DRV/r monotherapy arm and 100 of 106 (94%) in the triple therapy arm. There was no difference in neurocognitive function or the risk of neuropsychiatric adverse events between DRV/r monotherapy and triple therapy. Two patients in the monotherapy arm with CD4 nadir less than 200 cells/µl developed viraemia in both cerebrospinal fluid (CSF) and plasma, with one symptomatic case. CONCLUSIONS: In this study for patients with HIV-1 RNA less than 50 copies/ml at baseline, switching to DRV/r monotherapy showed lower efficacy versus triple therapy at week 48 in the primary ITT switch equals failure analysis, with two cases of viraemia in the CSF in the protease inhibitor monotherapy arm.

Effects of switching to protease inhibitor monotherapy on nucleoside analogue-related adverse events.

Switching from triple combination treatment to protease inhibitor monotherapy may increase the risk of elevations in HIV RNA, and is not recommended in most international treatment guidelines. However, the use of protease inhibitor monotherapy could prevent or reverse adverse events related to long-term use of nucleoside analogues, such as lipoatrophy, renal adverse events, osteopenia, and anemia. A detailed MEDLINE search was conducted to identify randomized clinical trials of triple-combination treatment versus protease inhibitor monotherapy with detailed analyses of safety. Summary results from analysis of changes in body composition, changes in lipids, renal adverse events, and anemia were evaluated for patients taking either protease inhibitor monotherapy or triple therapy. In six trials with dual-energy X-ray absorptiometry data available, the percentage of patients with lipoatrophy was significantly lower in the protease inhibitor monotherapy arms than the triple therapy arms (p = 0.03). In these trials there was also no significant difference in the risk of lipohypertrophy between protease inhibitor monotherapy and triple therapy arms. In one trial there was a higher risk of renal adverse events for patients taking tenofovir in the triple therapy arm. In two trials there were rises in total cholesterol when patients stopped taking tenofovir in the protease inhibitor monotherapy arms. In conclusion, there is a mixed pattern of changes in nucleoside analogue-related adverse events after switching from triple therapy to protease inhibitor therapy. The potential for safety benefits of stopping nucleoside analogues needs to be set against a higher risk of HIV RNA elevations during protease inhibitor monotherapy.

Morbidity in older HIV-infected patients: impact of long-term antiretroviral use.

The introduction of HAART has represented a major advance in the care of people with HIV. By markedly increasing life expectancy, HAART has significantly changed the pattern of HIV infection in developed countries, the "graying" of the HIV-infected population being a powerful testament to its success. However, this has presented physicians with new challenges relating to the care of older patients with HIV, many of whom exhibit a "frailty syndrome" associated with increased comorbidity and chronic low-grade inflammation in a process which has recently been termed "inflammaging". This paper reviews the pattern of morbidity seen in older HIV-infected patients and examines the effects, both beneficial and deleterious, of antiretroviral therapy. The efficacy and tolerability of antiretroviral therapy is of particular importance in older patients, given the likelihood that increased frailty may magnify the consequences both of suboptimal viral suppression and of toxicity, and in view of the complications that may arise from the presence of comorbidities and resultant polypharmacy. The challenge is to maximize antiviral efficacy and minimize toxicity, while taking into account the often complex web of comorbidities that may be present in these patients. This challenge is being met through the refinement of existing antiretroviral therapy regimens, the development of new agents, and a growing focus on a more holistic approach to care, which acknowledges the importance of the overall "health picture" and of good communication and cooperation between treating physicians and patients.

Etravirine as a Switching Option for Patients with HIV RNA Suppression: A Review of Recent Trials.

Unlike other nonnucleoside reverse transcriptase inhibitors, etravirine is only approved for use in treatment-experienced patients. In the DUET 1 and 2 trials, 1203 highly treatment-experienced patients were randomized to etravirine or placebo, in combination with darunavir/ritonavir and optimized background treatment. In these trials, etravirine showed significantly higher rates of HIV RNA suppression when compared with placebo (61% versus 40% at Week 48). There was no significant rise of lipids or neuropsychiatric adverse events, but there was an increase in the risk of rash with etravirine treatment. In the SENSE trial, which evaluated etravirine and efavirenz in 157 treatment-naïve patients in combination with 2 nucleoside analogues, there was a lower risk of lipid elevations and neuropsychiatric adverse events with etravirine when compared to efavirenz. Etravirine has been evaluated in three randomized switching studies. In the SSAT029 switch trial, 38 patients who had neuropsychiatric adverse events possibly related to efavirenz showed an improvement in these after switching to etravirine. The Swiss Switch-EE recruited 58 individuals without neuropsychiatric adverse events who were receiving efavirenz, and no benefit was shown when switching to etravirine. In the Spanish ETRA-SWITCH trial (n = 46), there were improvements in lipids when individuals switched from a protease inhibitor to etravirine. These switching trials were conducted in patients with full HIV RNA suppression: <50 copies/mL and with no history of virological failure or resistance to therapy. The results from these three randomized switching studies suggest a possible new role for etravirine, in combination with two nucleoside analogues, as a switching option for those with HIV RNA suppression but who are reporting adverse events possibly related to antiretroviral therapy. However a large well-powered trial would need to be conducted to strengthen the evidence from the pilot studies conducted so far.

No difference in the rate of change in telomere length or telomerase activity in HIV-infected patients after three years of darunavir/ritonavir with and without nucleoside analogues in the MONET trial.

OBJECTIVE: To determine whether nucleos(t)ide reverse transcriptase inhibitors (NRTI) contribute to an accelerated loss in telomere length (TL) in HIV-infected patients on antiretroviral therapy (ART). DESIGN: Substudy of randomised controlled trial. METHODS: Patients with HIV RNA <50 copies/mL on combination ART (n = 256) were randomised to darunavir/ritonavir (DRV/r) 800/100 mg once daily, either as monotherapy (n = 127) or with 2 NRTIs (n = 129) for up to 144 weeks. TL and telomerase activity was quantified on stored peripheral blood mononuclear cells (PBMC; n = 124) using quantitative real time PCR. RESULTS: Patients in the sub-study had a mean age of 44 years and had received NRTI for a mean of 6.4 years (range 1-20 years). As expected, older patients have significantly shorter TL (p = 0.006), while women had significantly longer TL (p = 0.026). There was no significant association between TL and either the duration of prior NRTI treatment (p = 0.894) or the use of a PI versus NNRTI (p = 0.107). There was no significant difference between patients who continued or ceased NRTI in the mean change/year of TL or telomerase (p = 0.580 and 0.280 respectively). CONCLUSION: Continuation versus cessation of NRTI treatment was not associated with an accelerated loss in TL or telomerase activity.

The PROTEA trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV-1 RNA below 50 copies/mL.

INTRODUCTION: In previous studies, protease inhibitor (PI) monotherapy has shown trends for higher low-level elevations in HIV-1 RNA compared to triple therapy, but no increase in the risk of drug resistance. METHODS: A total of 273 patients with HIV-1 RNA <50 copies/mL for over 24 weeks on current antiretrovirals switched to DRV/r (darunavir/ritonavir) 800/100 mg once-daily, either as monotherapy (n=137) or with 2NRTIs (nucleoside reverse-transcriptase inhibitors) (n=136), after a 4 week run-in phase with DRV/r + 2NRTI. Treatment failure was defined as HIV-1 RNA levels above 50 copies/mL (FDA Snapshot method) by Week 48, or switches off study treatment. Patients with elevations in HIV-1 RNA on DRV/r monotherapy could be re-intensified with NRTIs. The trial had 80% power to show non-inferiority for the monotherapy arm (delta = - 12%). RESULTS: Patients were 83% male and 87% Caucasian, with mean age 42 years; 10% were HCV antibody positive. In the DRV/r monotherapy arm, there were more patients with nadir CD4 count below 200 cells/µL (30% versus 22%). In the primary efficacy analysis, HIV-1 RNA <50 copies/mL by Week 48 (intent-to-treat (ITT)) was 118/137 (86.1%) in the DRV/r monotherapy arm versus 129/136 (94.9%) in the triple therapy arm; DRV/r monotherapy did not show non-inferiority versus triple therapy in the primary analysis (difference=- 8.7%, 95% CI -15.5 to -1.8%). In the multivariate analysis, the main predictor of treatment failure was nadir CD4 count. For patients with nadir CD4 counts <200 cells/µL, HIV-1 RNA suppression rates at Week 48 were 27/41 (66%) in the DRV/r monotherapy arm and 29/30 (97%) in the triple therapy arm; for patients with CD4 nadir at least 200 cells/µL, HIV-1 RNA suppression rates were 91/96 (95%) in the DRV/r monotherapy arm and 100/106 (94%) in the triple therapy arm. In the overall population, by a switch included analysis, efficacy was 92.0% versus 96.3%, showing non-inferiority (difference=- 4.3%, 95% CI=-9.7 to +1.2%). No treatment-emergent primary PI mutations were detected in three patients with sustained elevations in HIV-1 RNA at least 400 copies/mL (two on PI monotherapy, one on triple therapy). CD4 counts remained stable during the trial in both arms. CONCLUSIONS: In this study for patients with HIV-1 RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed lower efficacy versus triple antiretroviral therapy at Week 48 in the primary switch equals failure analysis (86% versus 95%). However, this lower efficacy was seen mainly in patients with CD4 nadir levels below 200 cells/µL. There was no development of PI resistance.

Analysis of neurocognitive function and CNS endpoints in the PROTEA trial: darunavir/ritonavir with or without nucleoside analogues.

INTRODUCTION: During treatment with protease inhibitor monotherapy, the number of antiretrovirals with therapeutic concentrations in the cerebrospinal fluid (CSF) is lower, compared to standard triple therapy. However, the clinical consequences are unclear. METHODS: A total of 273 patients with HIV RNA <50 copies/mL for over 24 weeks on current antiretrovirals randomized to darunavir/ritonavir (DRV/r) 800/100 mg once-daily, either as monotherapy (n=137) or with 2NRTIs (n=136). Neurocognitive function was evaluated in all patients by the Hopkins Verbal Learning Tests, the Colour Trail Tests and the Grooved Pegboard Test at screening, baseline and at Week 48. A global neurocognitive score (NPZ-5) was derived by averaging the standardized results of the five domains. In a central nervous system (CNS) sub-study (n=70), HIV RNA levels in the CNS were evaluated at baseline and Week 48. Clinical adverse events related to the CNS were collected at each visit. RESULTS: Patients were 83% male and 88% White, with median age 43 years. There were more patients with nadir CD4 count below 200 cells/µL in the DRV/r monotherapy arm (41/137, 30%) than the triple therapy arm (30/136, 22%). At Week 48, there was no difference between the treatment arms for the five combined domains of the neurocognitive score. At Week 48, the percentage of patients with an abnormal neurocognitive score among the five domains was 12.2% for DRV/r monotherapy and 14.9% for triple therapy. However, one patient on DRV/r monotherapy with a CD4 nadir of 17 cells/µL was hospitalized with HIV encephalomyelitis at Week 24, with HIV RNA 2500 copies/mL in the CSF and 125 copies/mL in the plasma. Symptoms resolved after intensification with high dose zidovudine. A second patient on DRV/r monotherapy with CD4 nadir of 166 cells/µL had a rise in HIV RNA in CSF from <40 copies/mL at baseline to 654 copies/mL at Week 48, with concurrent plasma HIV RNA of 77 copies/mL. CONCLUSIONS: In this study for patients with HIV RNA <50 copies/mL at baseline, there was no difference in neurocognitive function between the treatment arms. However two patients on PI monotherapy with CD4 nadir <200 cells/µL developed viraemia in both CSF and plasma, with one symptomatic case. DRV/r monotherapy should be used with caution in patients with nadir CD4 counts below 200 cells/µL.