Antiretroviral Treatment-experienced Patients Research Articles

Antiretroviral therapy and weight gain in antiretroviral treatment-experienced HIV patients: A review.

The risk of developing non-AIDS events (NAEs) remains higher in persons living with HIV-1 (PLWH) compared to the general population despite progress made in the treatment by antiretroviral (ARV). Particular attention is therefore given to the management of risk factors associated with NAEs during the follow-up of PLWH, including overweight. Factors associated with weight gain in PLWH are multifactorial and include demographics, HIV disease-related, lifestyle, cultural, and antiretroviral therapy (ART)-associated factors. All these confounding factors make it difficult to interpret the potential link between ARVs and weight gain. In antiretroviral treatment- experienced PLWH, confounding factors such as the return to normal health or the advanced stage of disease can be ruled out compared to naïve patients which somewhat facilitates the interpretation of weight gain. Weight gain after ART switch is modest, not generally a big concern in clinical practice in this population and correlated more strongly with baseline regimen, especially after the stop of TDF or EFV, than with sex-, race-, or HIV-related factors. It remains uncertain whether this is due to the loss of a weight suppressive effect of prior regimens with older agent such as TDF or EFV or a weight gain effect of the newer regimens especially TAF and/or INSTI, or both. The mechanisms linked to weight gain attributed to the new ARVs as well as its possible reversibility are not yet elucidated. Clinicians who switched ARV regimen of experienced PLWH should be aware of this side effect and of this potentially consequences on the global health.

Characterization of oral candidiasis according to antiretroviral treatment status, immunological and virological profiles among HIV infected patients in two health facilities in Yaoundé-Cameroon: a cross-sectional and analytical study.

oral candidiasis in HIV-disease generally indicates immune incompetence both among antiretroviral treatment (ART) naive and experienced patients. To optimize oral healthcare among people living with HIV (PLHIV) in sub-Saharan Africa (SSA), we sought to evaluate the type and distribution of oral candidiasis with respect to ART-profile and immuno-virological parameters among PLHIV in the Cameroonian context. a cross-sectional study was conducted among 163 patients (51 ART-naïve and 112 ART-experienced) residing in Yaoundé, Cameroon, from February through May 2019. Oral candidiasis was assessed, while viral load (VL) and CD4-count were measured on Abbott m2000rt and Cy-flow counter platforms, respectively. Data were analyzed using the Statistical Package for the Social Sciences (SPSS) v.21 with p<0.05 considered statistically significant. in all, 18 cases of two forms of oral candidiasis were identified (13 erythematous and 5 pseudomembranous), with the majority, 27.7% (11/51), observed among ART-naïve patients against 6.3% (7/112) in ART-experienced (p=0.006). With respect to immuno-virological profile, 77.8% (14/18) and 22.2% (4/18) of cases were identified among participants with CD4<200 cells/mm3 and CD4>200 cells/mm3, respectively (p<0.0001). In the light of viral load, the occurrence of oral candidiasis was largely observed among subjects with VL≥1000 copies/ml, 83.3% (15/18), against 16.7% (3/18), with VL<1000 copies/ml, irrespective of the candidiasis form (p<0.0001). among PLHIV, erythematous and pseudomembranous candidiasis are commonly found in the absence of ART, driven by immunodeficiency and active viral replication. In spite of the protective role of ART, PLHIV experiencing immuno-virological failure should be referred for management of oral candidiasis.

Persistent low-level viraemia in antiretroviral treatment-experienced patients is not linked to viral resistance or inadequate drug concentrations.

To assess genotypic sensitivity scores (GSSs), plasma antiretroviral concentrations (PACs) and immunovirological outcomes at Week 96 (W96) in patients with persistent low-level viraemia (LLV). On 1 January 2017, we analysed data from patients on three-drug regimens with persistent LLV defined as at least two consecutive plasma viral loads (pVLs) between 21 and 200 copies/mL (including one pVL of ≥50 copies/mL), at the Pitié-Salpêtrière Hospital. Outcomes were: GSS, PACs and HIV-DNA load at study entry; and virological status and proportion of patients with resistance-associated mutations (RAMs) at W96. Fifty-seven patients were included, with median age of 52.6 years (IQR 45.2-57.9), last CD4 count of 658 cells/mm3 (IQR 462-909) and total ART duration of 10.2 years (IQR 5.7-15.2). LLV duration was 14.0 months (IQR 5.5-22.3). GSS was 3 in 46/57 (81%) patients and PACs were adequate in 53/57 (93%) patients. Median total HIV-DNA was 2.65 log10 copies/106 cells (IQR 2.44-2.86). During follow-up, 26/57 (46%) had experienced ART modifications. At W96, 38/57 (67%) patients remained with LLV, 15/60 (26%) had achieved confirmed pVL of <20 copies/mL and 4/57 (7%) had virological failure. The four virological failures were due to three ART interruptions and one incomplete adherence (selection of Y181C RAM). No factors (patient characteristics at study entry, GSS, PACs, total HIV-DNA load and ART modification) were associated with W96 viral outcome, except for time from HIV diagnosis and the LLV duration at study entry. A substantial number of patients harbouring LLV had no resistance to ART and adequate PACs. Two-thirds of these patients remained with this LLV status.

Drug Resistance-Associated Mutations in Antiretroviral Treatment-Experienced Patients in Kuwait

Objectives: To investigate the prevalence of nonpolymorphic resistance-associated mutations (RAM) in HIV-1 patients on first-line antiretroviral therapy in Kuwait. Subjects and Methods: Total RNA was isolated from plasma samples of 42 patients who received a first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. HIV-1 protease and reverse transcriptase genetic regions were then amplified by nested reverse transcription-polymerase chain reaction and directly sequenced. The HIV-1 subtype was identified using the Bayesian phylogenetic method, and RAM were identified using the Stanford University genotypic resistance interpretation algorithm. Results: The HIV-1 viral load at sampling ranged from < 20 to 8.25 × 10⁴ copies/ml. CRF01_AE, C, and B were the most predominant HIV-1 subtypes. Nonpolymorphic mutations associated with resistance to antiretroviral drugs were detected in 11 (26.2%) of the 42 patients; 5 (11.9%) patients had mutations associated with a high-level resistance to nucleoside reverse transcriptase inhibitors (NRTI), 4 (9.5%) patients had mutations associated with resistance to NNRTI, 1 (2.4%) patient had mutations associated with resistance to both NRTI and NNRTI, and 1 (2.4%) patient had mutations potentially associated with low-level resistance to both protease inhibitors and NNRTI. All patients with RAM had a detectable plasma HIV-1 RNA level. Conclusion: Our results indicate the development of RAM during an NNRTI-based regimen and highlight the importance of considering other regimens to avoid treatment failure.

The Role of HIV-1 Drug-Resistant Minority Variants in Treatment Failure.

Human immunodeficiency virus type 1 (HIV-1) drug resistance genotyping is recommended to help in the selection of antiretroviral therapy and to prevent virologic failure. There are several ultrasensitive assays able to detect HIV-1 drug-resistance minority variants (DRMVs) not detectable by standard population sequencing-based HIV genotyping assays. Presence of these DRMVs has been shown to be clinically relevant, but its impact does not appear to be uniform across drug classes. In this review, we summarize key evidence for the clinical impact of DRMVs across drug classes for both antiretroviral treatment-naive and antiretroviral treatment-experienced patients, and highlight areas where more supporting evidence is needed.

High Prevalence of Cryptococcal Antigenaemia and Disseminated Cryptococcal Disease Amongst Patients with Advanced HIV Disease in Pune, India

Background The World Health Organization (WHO) recommends routine cryptococcal antigen (CrAg) screening in patients with advanced HIV disease initiating antiretroviral treatment (ART). India has yet to adopt this strategy as the burden of cryptococcal disease is unknown.Methods This was a prospective cohort study conducted between March 1, 2010 and March 1, 2017 at three private hospitals in Pune, India. All HIV-positive patients (symptomatic and asymptomatic) with CD4 counts ≤ 200 cells/µL were screened for serum cryptococcal antigen. Serum CrAg was measured using latex agglutination (LA) test. Both, ART naïve and ART experienced patients were included in the study. All HIV infected patients who were CrAg-positive were offered lumbar puncture (LP) and worked up for disseminated cryptococcal disease.ResultsA total of 785 HIV-positive patients (24.2% females) were included. Median age of cohort was 42 years (IQR, 35–49) and median CD4 count was 79 cells/mm3 (IQR, 37–82). 182/785(23.2%) patients were ART experienced. A total of 6.75% (53/785) of patients were CrAg positive in serum. Thirty-nine of 53 (73.6%) patients with positive serum cryptococcal antigen test had CD4 count ≤100 cells/mm3 while 14/53 (26.4%) had CD4 between 100 and 200 cells/mm3. Cerebrospinal fluid (CSF) CrAg was positive in 44/53(83%) patients. Two of 53(3.78%) had non-CNS, diffuse pulmonary cryptococcal disease and 7/53(13.2%) patients had isolated cryptococcal antigenemia. Patients with cryptococcal meningitis and crptococcal pulmonary disease were treated with Amphotericin-B plus oral Fluconazole. Patients with isolated cryptococcal antigenemia were treated with oral Fluconazole. Mortality at 6 months for patients with positive CrAg test was 22.6% (12/53).Conclusion We found 6.75% prevalence of cryptococcaemia amongst HIV patients with CD4 <200 cells/mm3. Given the high fatality rates observed, routine CrAg screening should be considered for all Indians with advanced HIV disease.Disclosures All authors: No reported disclosures.

Impact of etravirine use on hospitalization rates among highly pre-treated failing HIV-1 infected individuals between 2005 and 2011.

IntroductionEtravirine (ETR), a non-nucleoside reverse transcriptase inhibitor available in France since 2006, is indicated for the treatment of HIV-1 infection in combination with a ritonavir boosted protease inhibitor (PI) in antiretroviral treatment-experienced adult patients. To assess its impact in routine clinical care, our objective was to compare hospitalization rates in highly pre-treated failing HIV-1 infected individuals between 2005 and 2011 depending on whether or not they received ETR+PI.MethodsFrom the French Hospital Database on HIV (ANRS CO4), we selected highly pre-treated individuals (prior exposure to at least 2NRTI, 2PI and 1 NNRTI) with a viral load (VL)>50 copies/mL initiating a new regimen between 2005 and 2011. Hospitalization rates were calculated for each calendar month and depending on whether patients never received ETR+PI at any time or during months before initiating ETR+PI (no ETR+PI) or during months after initiating ETR+PI (ETR+PI), using an intention to continue treatment approach. Poisson regression models were used to compare incidence between the two groups, after adjustment for potential confounders (age, transmission group, origin, AIDS, PCP prophylaxis, viral load, CD4, nb of previous ARV).ResultsOverall 3884 patients fulfilled inclusion criteria. Among them 838 (21.6%) received ETR+PI at least once. Among all enrolled patients, 35.8% had CD4 <200/mm3, 17.5% had VL >100,000 copies/ml, 42.8% had had an AIDS event and 47.8% had received more than 10 different antiretroviral drugs. There were 2484 hospitalizations in 808 individuals over 13,986 patient-years. The hospitalization rates for 1000 P-Y were 169.0 for the ETR+PI group and 179.3 for the no ETR+PI group. After adjustment, the corresponding figures were 144.8 for 1000 P-Y and 192.7 for 1000 P-Y respectively, with a relative risk estimated as 0.75 (95% CI 0.67–0.84).ConclusionsAccess to ETR+PI between 2005 and 2011 was associated with a 25% reduction in the hospitalization rate among highly pre-treated failing HIV-1 infected individuals.

Estimating trends in the proportion of transmitted and acquired HIV drug resistance in a long term observational cohort in Germany.

ObjectiveWe assessed trends in the proportion of transmitted (TDR) and acquired (ADR) HIV drug resistance and associated mutations between 2001 and 2011 in the German ClinSurv-HIV Drug Resistance Study.MethodThe German ClinSurv-HIV Drug Resistance Study is a subset of the German ClinSurv-HIV Cohort. For the ClinSurv-HIV Drug Resistance Study all available sequences isolated from patients in five study centres of the long term observational ClinSurv-HIV Cohort were included. TDR was estimated using the first viral sequence of antiretroviral treatment (ART) naïve patients. One HIV sequence/patient/year of ART experienced patients was considered to estimate the proportion of ADR. Trends in the proportion of HIV drug resistance were calculated by logistic regression.Results9,528 patients were included into the analysis. HIV-sequences of antiretroviral naïve and treatment experienced patients were available from 34% (3,267/9,528) of patients. The proportion of TDR over time was stable at 10.4% (95% CI 9.1–11.8; p for trend = 0.6; 2001–2011). The proportion of ADR among all treated patients was 16%, whereas it was high among those with available HIV genotypic resistance test (64%; 1,310/2,049 sequences; 95% CI 62–66) but declined significantly over time (OR 0.8; 95% CI 0.77–0.83; p for trend<0.001; 2001–2011). Viral load monitoring subsequent to resistance testing was performed in the majority of treated patients (96%) and most of them (67%) were treated successfully.ConclusionsThe proportion of TDR was stable in this study population. ADR declined significantly over time. This decline might have been influenced by broader resistance testing, resistance test guided therapy and the availability of more therapeutic options and not by a decline in the proportion of TDR within the study population.

Prevalence of R5 and X4 HIV variants in antiretroviral treatment experienced patients with virologic failure

BackgroundAntiretroviral therapy (ART) inhibits virus replication. Nevertheless, ART has the disadvantage of generate selective resistance and adverse events. Coreceptor antagonists are a family of antiretroviral drugs that are used with the prior knowledge of patients HIV tropism. ObjectivesThe purpose of this work was to estimate the prevalence of R5 and X4 variants among Chilean patients under antiretroviral therapy and virological failure and investigate variables such as plasma viral load (pVL) and CD4 cell count in the population studied. Study designHIV RNA or proviral DNA was extracted from 454 consecutives patients and tropism testing was performed using a genotypic method performed with Geno2pheno setting a cutoff value for FPR 5.75%. ResultsAmong 454 individuals analyzed, 299 (66%) harbouring exclusively R5 variants. They not displayed a better clinical profile than individuals harbouring X4 strains (22%). For R5 patients the median of pVL and CD4 cell count were 268,000copies/mL, and 223cells/μL respectively. For X4 samples the values were 368,000copies/mL and 214cells/μL [P>0.05]). Only, 53 patients (12%) could not be analyzed and were categorized as non-reportable. ConclusionsThe genotypic method confirmed that R5 strains were more prevalent despite the fact that patients were treatment-experienced for several years. The genotypic strategy proved to be a faster and cost-effective option as compared to phenotypic assays. According to our results, two of every three patients under antiretroviral therapy and with virologic failure harbour R5 strains, and may be candidates for use of a CCR5 antagonist.

Complex Patterns of Protease Inhibitor Resistance among Antiretroviral Treatment-Experienced HIV-2 Patients from Senegal: Implications for Second-Line Therapy

Protease inhibitor (PI)-based antiretroviral therapy (ART) can effectively suppress HIV-2 plasma load and increase CD4 counts; however, not all PIs are equally active against HIV-2, and few data exist to support second-line therapy decisions. To identify therapeutic options for HIV-2 patients failing ART, we evaluated the frequency of PI resistance-associated amino acid changes in HIV-2 sequences from a cohort of 43 Senegalese individuals receiving unboosted indinavir (n = 18 subjects)-, lopinavir/ritonavir (n = 4)-, or indinavir and then lopinavir/ritonavir (n = 21)-containing ART. Common protease substitutions included V10I, V47A, I54M, V71I, I82F, I84V, L90M, and L99F, and most patients harbored viruses containing multiple changes. Based on genotypic data, we constructed a panel of 15 site-directed mutants of HIV-2ROD9 containing single- or multiple-treatment-associated amino acid changes in the protease-encoding region of pol. We then quantified the susceptibilities of the mutants to the HIV-2 "active" PIs saquinavir, lopinavir, and darunavir using a single-cycle assay. Relative to wild-type HIV-2, the V47A mutant was resistant to lopinavir (6.3-fold increase in the mean 50% effective concentration [EC50]), the I54M variant was resistant to darunavir and lopinavir (6.2- and 2.7-fold increases, respectively), and the L90M mutant was resistant to saquinavir (3.6-fold increase). In addition, the triple mutant that included I54M plus I84V plus L90M was resistant to all three PIs (31-, 10-, and 3.8-fold increases in the mean EC50 for darunavir, saquinavir, and lopinavir, respectively). Taken together, our data demonstrate that PI-treated HIV-2 patients frequently harbor viruses that exhibit complex patterns of PI cross-resistance. These findings suggest that sequential PI-based regimens for HIV-2 treatment may be ineffective.

Subgroup analysis of virological response rates with once- and twice-daily darunavir/ritonavir in treatment-experienced patients without darunavir resistance-associated mutations in the ODIN trial

ODIN (once-daily darunavir in treatment-experienced patients) was a 48-week, phase III, randomized, open-label trial comparing once-daily (qd) darunavir/ritonavir (DRV/r) 800/100 mg with twice-daily (bid) DRV/r 600/100 mg, both with an optimized background regimen [OBR; at least two nucleoside reverse transcriptase inhibitors (NRTIs)], in treatment-experienced, HIV-1-infected adults with no DRV resistance-associated mutations (RAMs) at screening. Week 48 analyses of virological response by subgroups are reported. A total of 590 patients were randomized to receive qd (n=294) or bid (n=296) DRV/r. Virological response (HIV-1 RNA <50 copies/mL) was assessed according to: screening HIV-1 RNA (≥ or <50000 copies/mL), CD4 cell count, prior protease inhibitor (PI) use, number of active NRTIs in the OBR, presence of mutations (primary PI mutations, PI RAMs or M184V/I), gender, age, race, HIV-1 clade and adherence. Baseline characteristics were well balanced between arms and across subgroups. Response rates were comparable between qd and bid DRV/r treatments for all subgroups examined. Response rates were 78.4 and 76.8% in the qd and bid treatment arms, respectively, in patients with baseline HIV-1 RNA ≤ 50000 copies/mL and 52.8% in both arms in those with > 50000 copies/mL. Response rates for the qd and bid treatment arms by baseline CD4 cell count were also similar (69.6 vs. 65.2% for <200 cells/μL; 72.2 vs. 74.8% for 200- <350 cells/μL; 77.0 vs. 74.3% for ≥ 350 cells/μL). DRV/r administered either qd or bid provided effective treatment for antiretroviral treatment-experienced patients with no DRV RAMs, with comparable response rates across all subgroups studied. Low patient numbers in specific subgroups may limit interpretation of these specific subgroup results.

HIV-1 integrase resistance among antiretroviral treatment naive and experienced patients from Northwestern Poland

BackgroundHIV integrase inhibitor use is limited by low genetic barrier to resistance and possible cross-resistance among representatives of this class of antiretrovirals. The aim of this study was to analyse integrase sequence variability among antiretroviral treatment naive and experienced patients with no prior integrase inhibitor (InI) exposure and investigate development of the InI drug resistance mutations following the virologic failure of the raltegravir containing regimen.MethodsSequencing of HIV-1 integrase region from plasma samples of 80 integrase treatment naive patients and serial samples from 12 patients with observed virologic failure on raltegravir containing treatment whenever plasma vireamia exceeded >50 copies/ml was performed. Drug resistance mutations were called with Stanford DB database and grouped into major and minor variants. For subtyping bootstrapped phylogenetic analysis was used; Bayesian Monte Carlo Marcov Chain (MCMC) model was implemented to infer on the phylogenetic relationships between the serial sequences from patients failing on raltegravir.ResultsMajority of the integrase region sequences were classified as subtype B; the remaining ones being subtype D, C, G, as well as CRF01_AE , CRF02_AG and CRF13_cpx recombinants. No major integrase drug resistance mutations have been observed in InI-treatment naive patients. In 30 (38.5%) cases polymorphic variation with predominance of the E157Q mutation was observed. This mutation was more common among subtype B (26 cases, 54.2%) than non-B sequences (5 cases, 16.7%), p=0.00099, OR: 5.91 (95% CI:1.77-22.63)]. Other variants included L68V, L74IL, T97A, E138D, V151I, R263K. Among 12 (26.1%) raltegravir treated patients treatment failure was observed; major InI drug resistance mutations (G140S, Q148H and N155H, V151I, E92EQ, V151I, G163R) were noted in four of these cases (8.3% of the total InI-treated patients). Time to the development of drug resistance ranged from 2.6 to 16.3 months with mean increase of HIV viral load of 4.34 (95% CI:1.86-6.84) log HIV-RNA copies/ml at the time of emergence of the major mutations. Baseline polymorphisms, including E157Q were not associated with the virologic failure on raltegravir.ConclusionsIn InI treatment naive patients polymorphic integrase sequence variation was common, with no major resistance mutants. In the treatment failing patients selection of drug resistance occurred rapidly and followed the typical drug resistance pathways. Preexisting integrase polymorphisms were not associated with the treatment failure.

The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment

The availability of 24 antiretroviral (ARV) drugs within six distinct drug classes has transformed HIV-1 infection (AIDS) into a treatable chronic disease. However, the ability of HIV-1 to develop resistance to multiple classes continues to present challenges to the treatment of many ARV treatment-experienced patients. In this case report, we describe the response to ibalizumab, an investigational CD4-binding monoclonal antibody (mAb), in a patient with advanced immunodeficiency and high-level five-class antiretroviral resistance. After starting an ibalizumab-based salvage regimen, the patient had an approximately 4.0 log10 reduction in viral load. An inadvertently missed infusion at week 32 led to the rapid loss of virologic response and decreased susceptibility to the remainder of the patient’s salvage therapy regimen. Following the reinstitution of ibalizumab, phenotypic and genotypic resistance to ibalizumab was detected. Nonetheless, plasma HIV-1 RNA levels stabilized at ∼2.0 log10 copies/ml below pre-ibalizumab levels. Continued ARV drug development may yield additional clinical and public health benefits. This report illustrates the promise of mAbs for HIV-1 therapy in highly treatment-experienced patients. Therapeutic mAbs may also have a role in pre-exposure prophylaxis in high-risk uninfected populations and may facilitate directly observed therapy (DOT) if two or more synergistic long acting agents become available.

Tipranavir in highly antiretroviral treatment-experienced patients: Results from a French prospective cohort

In highly antiretroviral-experienced patients with a multidrug-resistant human immunodeficiency virus (HIV) infection, recommended regimens should preferentially contain 3 active components, including a ritonavir-boosted protease inhibitor (PI/r). Tipranavir/r (TPV/r), a non-peptidic PI, has been specifically developed for patients resistant to the usual antiretroviral classes including PIs. This paper discusses the role of TPV/r in patients experiencing multiple PI resistance. Virological, immunological, and safety outcomes were collected between 2003 and 2007 at 7 clinical units. Virus resistance assessment was based on 3 different genotypic tests. The 207 patients evaluated had previously received nucleoside reverse transcriptase inhibitors (NRTIs) and PIs. The main drugs co-administered with TPV/r were 1 or 2 NRTIs associated, in half of the patients, with enfuvirtide. After 12 weeks, viral load was <50 copies/ml in 38% of the patients (44% with enfuvirtide), while median CD4 counts had increased from 150 to 250 cells/mm³. Genotypic testing suggested that most of the patients had viruses susceptible to TPV. Lipid and transaminase levels were slightly modified, and less than 10% of treatment discontinuations were due to gastrointestinal events. A regimen including TPV/r associated with at least 1 active component is a valuable option in highly ARV-experienced patients with multi-resistance to the usual ARV classes including PIs.

Lessons from maraviroc clinical trials

Evaluation of: Gulick RM, Lalezari J, Goodrich J et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N. Engl. J. Med. 359, 1429–1441 (2008).Maraviroc is the first commercially available HIV chemokine receptor antagonist targeting HIV that utilizes the CCR5 chemokine receptor (R5 tropic). The Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) trials were two randomized, placebo-controlled studies designed to demonstrate the activity of maraviroc in triple-class-experienced HIV individuals, with a primary end point of viral load suppression at 48 weeks. Maraviroc outperformed the placebo plus optimized background (OBT) arm, and exhibited a favorable safety profile with low discontinuation rates, which equaled those of the placebo plus OBT group. The results of these trials led to maraviroc receiving regulatory approval for the treatment of HIV.

Deep Sequencing to Infer HIV-1 Co-Receptor Usage: Application to Three Clinical Trials of Maraviroc in Treatment-Experienced Patients

The Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) studies compared maraviroc versus placebo in treatment-experienced patients with CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1), screened using the original Trofile assay. A subset with non-R5 HIV infection entered the A4001029 trial. We retrospectively examined the performance of a genotypic tropism assay based on deep sequencing of the HIV env V3 loop in predicting virologic response to maraviroc in these trials. V3 amplicons were prepared from 1827 screening plasma samples and sequenced on a Roche/454 GS-FLX to a depth of >3000 sequences/sample. Samples were considered non-R5 if ≥2% of their viral population scored greater than or equal to -4.75 or ≤3.5 using the PSSM(x4/R5) or geno2pheno algorithms, respectively. Deep sequencing identified more than twice as many maraviroc recipients as having non-R5 HIV, compared with the original Trofile. With use of genotyping, we determined that 49% of maraviroc recipients with R5 HIV at screening had a week 48 viral load <50 copies/mL versus 26% of recipients with non-R5. Corresponding percentages were 46% and 23% with screening by Trofile. In cases in which screening assays differed, median week 8 log₁₀ copies/mL viral load decrease favored 454. Other parameters predicted by genotyping included likelihood of changing to non-R5 tropism. This large study establishes deep V3 sequencing as a promising tool for identifying treatment-experienced individuals who could benefit from CCR5-antagonist-containing regimens.

Genotypic Tests for Determining Coreceptor Usage of HIV-1

Genotypic Tests for Determining Coreceptor Usage of HIV-1

Cost-effectiveness of optimized background therapy plus maraviroc for previously treated patients with R5 HIV-1 infection from the perspective of the Spanish health care system

Objective: The aim of this work was to evaluate the cost-effectiveness, from the perspective of the Spanish health care system, of optimized background therapy (OBT) plus maraviroc 300 mg BID versus OBT plus placebo in previously treated patients with R5 HIV-1 infection. Methods: A lifetime cohort model was developed, based on 24- and 48-week pooled results from the Maraviroc Versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) studies 1 and 2, to reflect the Spanish health care system's perspective. Treatment duration was based on clinical trial follow-up from MOTIVATE 1 and 2. Clinical data, cohort characteristics, success probability, CD4 increase rate, CD4 cell status link to disease states, and adverse-event probability were taken from the MOTIVATE trials and other published literature. Other input parameters were taken from published sources. Antiretroviral (ARV) costs were derived from local sources. Non-ARV drug costs were obtained from published literature and a cost database. All costs were calculated as year-2009 euros. The annual discount rate was set at 3.0%. The main outcomes were cost per life-year gained (LYG) and cost per quality-adjusted life-year (QALY) gained. Uncertainty was assessed with one-way and probabilistic sensitivity analyses. Results: In the model analysis, adding maraviroc to OBT was associated with an increase of 0.952 LYG and 0.909 QALY. Total costs were €275,970 for maraviroc plus OBT and €254,655 for placebo plus OBT (difference: €21,315). The incremental cost per LYG was €22,398 and the incremental cost per QALY gained was €23,457. The model appeared to be robust for variations in key parameters. Results from the probabilistic sensitivity analyses indicated that the probability of the cost per QALY being below €30,000 was 99%. Conclusion: Despite the limitations of the model, our analysis suggested that OBT plus maraviroc 300 mg BID is a clinically valuable option, and cost-effective from the perspective of the Spanish health care system, for previously treated patients with R5 HIV-1 infection.

Raltegravir and unboosted atazanavir dual therapy in virologically suppressed antiretroviral treatment-experienced HIV patients

Because of the favourable safety and tolerability profiles of atazanavir (ATV) and raltegravir (RAL), attention has recently turned to the use of dual ATV plus RAL therapy as a nucleoside reverse transcriptase inhibitor-sparing treatment strategy in highly antiretroviral treatment (ART)-experienced HIV-infected patients. A retrospective observational study was carried out to assess the maintenance of viral suppression and ART tolerability in 20 highly ART-experienced patients with viral suppression, who had been switched to RAL and unboosted ATV dual therapy, using data collected during standard-of-care visits. At 6, 12 and 18 months, viral load was maintained at <400 HIV RNA copies/ml, with only one participant recording a detectable viral load (150 copies/ml) at the 6-month time point. Stable CD4(+) T-cell counts were maintained throughout the study period. Five participants changed regimen during the 18-month follow-up, with the median time to switch being 9 months (range 2-12). In three cases, patients were changed from dual therapy because of adverse events while on the regimen. These included increased fatigue (two patients), persistently increased bilirubin (one patient) and gastrointestinal side effects (one patient). Two additional patients changed therapy: one patient added lamivudine and one ceased ATV to pre-empt a potential drug-drug interaction. All five patients who switched from ATV/RAL before 12 months follow-up maintained viral suppression, implying no disadvantage from switching to dual therapy. Dual therapy with ATV plus RAL maintained viral suppression in this small group of highly ART-experienced patients. Further investigation of this novel dual therapy regimen is warranted.

The next generation: etravirine in the treatment of HIV-1 infection in adults refractory to other antiretrovirals

Correspondence: Michelle D Liedtke 1110 N. Stonewall, CPB 229, Oklahoma City, OK 73117, USA Tel +1 405 271 6878 ext 47260 Fax +1 405 271 6430 email michelle-liedtke@ouhsc.edu Abstract: Etravirine is a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) that is approved for the treatment of adult human immunodeficiency virus (HIV)infected patients with documented or suspected resistance to first-generation NNRTIs. Etravirine has a flexible molecular structure that allows it to retain its activity against mutant HIV strains that exhibit resistance to first-generation agents. It is evident that 3 or more etravirine resistance-associated mutations are typically necessary before clinical resistance to etravirine. Safety and efficacy of etravirine are established in antiretroviral treatment-experienced patients in combination with antiretroviral regimens that contain darunavir/ritonavir. In phase III studies, cutaneous reactions occurred in 19% of treated patients and are the most commonly observed adverse event. The typical manifestation is the development of a maculopapular rash within the first few weeks of etravirine therapy. Resolution commonly occurs within 1–2 weeks on continued therapy. Rare cases of severe skin reactions (,0.1%) have been reported. Etravirine is hepatically metabolized by cytochrome P450 (CYP) 3A4, CYP2C9, and CYP2C19. Drug interactions with some antiretrovirals (eg, unboosted protease inhibitors and fosamprenavir/ ritonavir) and medications for other comorbidities (eg, atorvastatin and clarithromycin) have been reported and may require dosage adjustment for the coadministered drug or selection of alternative therapy in some instances. Administration of etravirine with potent inducers of CYP450 is not recommended due to the potential for subtherapeutic etravirine concentrations. In this article, the pharmacology, efficacy, safety, and tolerability of etravirine in adult treatmentexperienced patients with HIV-1 infection are reviewed. Medical literature was identified by MEDLINE and EMBASE searches (1966 to February 2010) using the search terms “etravirine”, “TMC125”, and “NNRTI”.