Genotypic tropism testing in proviral DNA to guide maraviroc initiation in aviremic subjects: 48-week analysis of the PROTEST study.

INTRODUCTION: In a previous interim 24-week virological safety analysis of the PROTEST study (1), initiation of Maraviroc (MVC) plus 2 nucleoside reverse-transcriptase inhibitors (NRTIs) in aviremic subjects based on genotypic tropism testing of proviral HIV-1 DNA was associated with low rates of virological failure. Here we present the final 48-week analysis of the study. METHODS: PROTEST was a phase 4, prospective, single-arm clinical trial (ID: NCT01378910) carried on in 24 HIV care centres in Spain. Maraviroc-naïve HIV-1-positive adults with HIV-1 RNA (VL) <50 c/mL on stable ART during the previous 6 months, requiring an ART change due to toxicity, with no antiretroviral resistance to the ART started, and R5 HIV by proviral DNA genotypic tropism testing (defined as a G2P FPR >10% in a singleton), initiated MVC with 2 NRTIs and were followed for 48 weeks. Virological failure was defined as two consecutive VL>50 c/mL. Recent adherence was calculated as: (# pills taken/# pills prescribed during the previous week)*100. RESULTS: Tropism results were available from 141/175 (80.6%) subjects screened: 87/141 (60%) were R5 and 74/87 (85%) were finally included in the study. Their median age was 48 years, 16% were women, 31% were MSM, 36% had CDC category C at study entry, 62% were HCV+ and 10% were HBV+. Median CD4+ counts were 616 cells/mm(3) at screening, and median nadir CD4+ counts were 143 cells/mm(3). Previous ART included PIs in 46 (62%) subjects, NNRTIs in 27 (36%) and integrase inhibitors (INIs) in 1 (2%). The main reasons for treatment change were dyslipidemia (42%), gastrointestinal symptoms (22%), and liver toxicity (15%). MVC was given alongside TDF/FTC in 40 (54%) subjects, ABC/3TC in 30 (40%), AZT/3TC in 2 (3%) and ABC/TDF in 2 (3%). Sixty-two (84%) subjects maintained VL<50 c/mL through week 48, whereas 12 (16%) discontinued treatment: two (3%) withdrew informed consent, one (1%) had a R5→X4 shift in HIV tropism between the screening and baseline visits, one (1%) was lost to follow-up, one (1%) developed an ART-related adverse event (rash), two (3%) died due to non-study-related causes (1 myocardial infarction at week 0 and 1 lung cancer at week 36), and five (7%) developed protocol-defined virological failure, although two of them regained VL<50 c/mL with the same MVC regimen (Table 1). CONCLUSIONS: Initiation of MVC plus 2 NRTIs in aviremic subjects based on genotypic tropism testing of proviral HIV-1 DNA is associated with low rates of virological failure up to one year.

Impact of drug resistance genotypes on CD4+ counts and plasma viremia in heavily antiretroviral-experienced HIV-infected patients.

The number of HIV-infected individuals with prior multiple treatment failures is increasing as time passes by. The success of antiretroviral therapy in these patients is often compromised by the selection of drug-resistant viruses. Despite initial concerns, a rebound in AIDS cases among heavily treatment-experienced patients failing virologically their antiretroviral therapy has not occurred yet. In a multicenter study conducted in Spain, HIV-infected patients were assessed with prior failure to antiretrovirals from the three main drug families who presented during the last semester of the year 2003 with plasma HIV-RNA values above 1,000 copies/ml, despite good treatment adherence. The relationships between CD4+ T cell counts, viral loads and drug-resistant genotypes were examined. A total of 273 patients were identified in 12 centers (78% male, median age: 41 years). The mean viral load was 50,438 copies/ml and the mean CD4+ count was 328 cells/mul. Only 19.5% had less than 200 CD4+ T cells/mul. Most patients (95%) were receiving nucleoside reverse transcriptase inhibitors (NRTI) in their last antiretroviral regimen, while 63% were treated with protease inhibitors (PI) and 27% on non-nucleoside reverse transcriptase inhibitors (NNRTI). Overall, 97.4% had at least one drug resistance mutation (87.2% for NRTI, 68.5% for NNRTI, and 92.7% for PI). Using the virtual phenotype, resistance to three or more drugs within each class was recognized in 45.8% for NRTI, 40.7% for NNRTI, and 44.7% for PI. Moreover, cross-resistance to compounds from two or three drug families was recognized in 41% and 19.4% of patients, respectively. Nearly half of the patients had plasma HIV-RNA below 10,000 copies/ml and they showed significantly higher CD4 + counts than those with greater viremia (408 versus 259 cells/mul; P < 0.001). Patients with higher plasma viremia had significantly more drug resistance mutations than those with lower viremia. No favorable effect on viral load could be recognized for individual drug resistance mutations known to reduce viral fitness in vitro (i.e., rtM184V, rtL74V, rtK65R, proD30N, or proI50L). In summary, a large proportion of treatment-experienced patients failing their current antiretroviral regimen carry viruses with broad cross-resistant genotypes. Nearly half of the patients with these multi-drug resistant viruses had < 10,000 HIV-RNA copies/ml and 80% have more than 200 CD4 + T cells/mul. Thus, maintaining treatment HIV-infected individuals failing virologically and harboring drug-resistant viruses might ameliorate immunological deterioration until new drugs became available. J. Med. Virol. 77:23-28, 2005. (c) 2005 Wiley-Liss, Inc.

Aproximación al tratamiento del paciente en situación de multifracaso / Approach to treatment of patients with virologic failure to multiple regimens

Los tratamientos de rescate en pacientes en multifracaso conseguirán la supresión de la replicación viral en el 30-45% de los pacientes. Para mejorar estos resultados antes de cambiar el tratamiento en estos pacientes deben valorarse pros y contras de las distintas opciones terapéuticas, ponerse unos objetivos terapéuticos factibles e intentar conocer las causas de fracasos previos. Para ello, debe disponerse de la carga viral inicial y actual, los linfocitos CD4, tratamientos antirretrovirales previos y efectos adversos a los mismos, estudios de resistencias y valoración de la adherencia y disposición al cambio del paciente. Probablemente es importante poder disponer de los niveles de los fármacos de rescate y el cociente inhibitorio (IQ) de los mismos. En pacientes con carga viral plasmática (CVP)-VIH-1 moderada (< 5.000 copias/ml), principalmente si se mantienen estables, las posibilidades de deterioro clínico e inmunológico son escasas a corto plazo, siendo prudente esperar si las posibilidades de conseguir suprimir la replicación viral son escasas. En pacientes en multifracaso debe cambiarse de forma simultánea como mínimo dos fármacos nuevos a los que el virus no sea resistente, utilizando fármacos con elevada potencia y con regímenes que aseguren niveles plasmáticos elevados. En pacientes con múltiples tratamientos previos se está estudiando la utilidad de la interrupción temporal del tratamiento antes de iniciar una pauta de rescate. Nuevos fármacos antirretrovirales como el DAPD, tenofovir (TNF), TMC 120, lopinavir (LPV), tipranavir (TPV) o T-20 pueden ser especialmente útiles en el tratamiento de estos pacientes (AU)

Second-line and rescue antiretrovirals regimens have a poor success record only 30-45% achieves viral suppression. This rate will be improved if salvage therapy is individualized with a better understanding what causes previous failures, establishing reasonable goals of therapy for the patient and speaking with him about the pros and the cons of the new regimens. Before deciding the change we must have available the first and the present HIV RNA levels, absolute CD4 T cell count and changes in these counts, prior antiretroviral therapies, resistance test, assessment of adherence to medications, and preparation of the patient for the implications of the new regimens. Carrying out drug salvage levels and the inhibitory quotient probably can be important. In patients on therapy with detectable but low (< 5,000 copies/ml) stable HIV RNA levels the risk of clinical or immunologic failure is low. Recent reports provide support for a conservative strategy, particularly for those patients with limited therapeutic options. In-patients who are failing their second regimen it is important to use at least two new susceptible drugs, with a high potency and using combinations that assure high drug levels. In this population treatment interruption as a strategy for managing drug resistance is in study. New therapies such as DAPD, tenofovir, TMC 120, lopinavir, tipranavir and T-20 offer significant promise for the treatment of drug-experienced patients (AU)