Primary resistance to integrase strand transfer inhibitors in Spain using ultrasensitive HIV-1 genotyping.

BACKGROUND: Transmission of resistance mutations to integrase strand transfer inhibitors (INSTIs) in HIV-infected patients may compromise the efficacy of first-line antiretroviral regimens currently recommended worldwide. Continued surveillance of transmitted drug resistance (TDR) is thus warranted. OBJECTIVES: We evaluated the rates and effects on virological outcomes of TDR in a 96 week prospective multicentre cohort study of ART-naive HIV-1-infected subjects initiating INSTI-based ART in Spain between April 2015 and December 2016. METHODS: Pre-ART plasma samples were genotyped for integrase, protease and reverse transcriptase resistance using Sanger population sequencing or MiSeq™ using a ≥ 20% mutant sensitivity cut-off. Those present at 1%-19% of the virus population were considered to be low-frequency variants. RESULTS: From a total of 214 available samples, 173 (80.8%), 210 (98.1%) and 214 (100.0%) were successfully amplified for integrase, reverse transcriptase and protease genes, respectively. Using a Sanger-like cut-off, the overall prevalence of any TDR, INSTI-, NRTI-, NNRTI- and protease inhibitor (PI)-associated mutations was 13.1%, 1.7%, 3.8%, 7.1% and 0.9%, respectively. Only three (1.7%) subjects had INSTI TDR (R263K, E138K and G163R), while minority variants with integrase TDR were detected in 9.6% of subjects. There were no virological failures during 96 weeks of follow-up in subjects harbouring TDR as majority variants. CONCLUSIONS: Transmitted INSTI resistance remains rare in Spain and, to date, is not associated with virological failure to first-line INSTI-based regimens.

Simplification to dual therapy (atazanavir/ritonavir + lamivudine) versus standard triple therapy [atazanavir/ritonavir + two nucleos(t)ides] in virologically stable patients on antiretroviral therapy: 96 week results from an open-label, non-inferiority, randomized clinical trial (SALT study).

OBJECTIVES: We evaluated whether maintenance therapy with atazanavir/ritonavir plus lamivudine (ATV/r + 3TC) was non-inferior to ATV/r plus two nucleosides (ATV/r + 2NUCs) at 96 weeks of follow-up. METHODS: SALT is a multicentre, open-label, non-inferiority clinical trial in HIV-1-infected virologically suppressed patients. Hepatitis B virus surface antigen-negative subjects with no previous treatment failure/resistance mutations and HIV-1-RNA <50 copies/mL for ≥6 months were randomized (1 : 1) to ATV/r + 3TC or ATV/r + 2NUCs. The primary endpoint was HIV-1-RNA <50 copies/mL in the PP population. Non-inferiority was demonstrated if the lower bound of the 95% CI for the difference was not below -12%. RESULTS: Some 286 patients were analysed. At week 96, 74.4% had HIV-1-RNA <50 copies/mL in the ATV/r + 3TC arm versus 73.9% in the ATV/r + 2NUCs arm (95% CI for the difference, -9.9%-11.0%). In both groups, similar values were observed for patients with confirmed virological failure in ATV/r + 3TC versus ATV/r + 2NUCs (9 versus 5), death (1 versus 0), discontinuation due to ART-related toxicity (7 versus 11), withdrawal from the study (7 versus 9) and loss to follow-up (6 versus 6). One patient taking ATV/r + 2NUCs developed resistance mutations (M184V and L63P). Similar values were obtained for change in mean CD4 count [19 versus 18 cells/mm3 (95% CI for the difference, -49.3-50.7), grade 3-4 adverse events (70.7% versus 70.2%) and changes in the global deficit score, -0.3 (95% CI, -0.5 to -0.1) for ATV/r + 3TC, versus -0.2 (95% CI, -0.4 to -0.1) for ATV/r + 2NUCs]. CONCLUSIONS: The long-term results of switching to ATV/r + 3TC show that this strategy is effective, safe and non-inferior to ATV + 2NUCs in virologically suppressed HIV-infected patients.

The role of tenofovir alafenamide in future HIV management.

HIV infection has become a chronic condition rather than an acute life-threatening disease in developed countries, thanks to consistent innovation and evolution of effective interventions. This has altered HIV management and created new challenges. People living with HIV (PLWHIV) are living longer and so encounter comorbidities linked not only with their disease, but also with ageing, lifestyle and chronic exposure to antiretroviral therapy (ART). Although longevity, viral suppression and the prevention of viral transmission remain key goals, more needs to be achieved to encompass the vision of attaining an optimum level of overall health. Treatment choices and management practices should ensure patients' long-term health with minimal comorbidity. Treatments that balance optimal efficacy with the potential for improved long-term safety are needed for all patients. In this review, we consider the evolution and development of tenofovir alafenamide (TAF), a novel prodrug of tenofovir which offers high antiviral efficacy at doses over ten times lower than that of tenofovir disoproxil fumarate (TDF). Emerging clinical data suggest that elvitegravir, cobicistat, emtricitabine and TAF (E/C/F/TAF) as a single-tablet regimen offers highly effective viral suppression in treatment-naïve and treatment-experienced patients with an improved renal and bone safety profile compared with TDF, this having been demonstrated in diverse groups including patients with existing renal impairment and adolescents. The profile of TAF identifies it as an agent with a promising role within future ART regimens that aim to deliver the vision of undetectable viral load, while requiring less monitoring and having a safety profile designed to minimize comorbid risks while supporting good long-term health.

Interpreting the reasons for the choice and changing of two drug regimens in an observational cohort: comparison of a ritonavir-boosted protease inhibitor-based versus a nonnucleoside reverse transcriptase inhibitor-based first-line regimen.

OBJECTIVES: We compared reasons for the choice of regimen, time to and reasons for third drug modification, virological response and change in CD4 T-cell counts in patients started on atazanavir/ritonavir (ATV/r)- vs. efavirenz (EFV)-based first-line regimens. METHODS: We included patients from the Cohort of the Spanish HIV Research Network (CoRIS), a multicentre cohort of HIV-positive treatment-naïve subjects, in the study. We used logistic regression to assess factors associated with choosing ATV/r vs. EFV, proportional hazards models on the subdistribution hazard to estimate subdistribution hazard ratios (sHRs) for third drug modification, logistic regression to estimate odds ratios (ORs) for virological response and linear regression to assess mean differences in CD4 T-cell count increase from baseline. RESULTS: Of 2167 patients, 10.7% started on ATV/r. ATV/r was more likely than EFV to be prescribed in injecting drug users [adjusted OR 1.85; 95% confidence interval (CI) 1.03-3.33], in 2009-2010 (adjusted OR 1.63; 95% CI 1.08-2.47) and combined with abacavir plus lamivudine (adjusted OR 1.53; 95% CI 0.98-2.43). Multivariate analyses showed no differences, comparing ATV/r vs. EFV, in the risk of third drug modification (sHR 1.04; 95% CI 0.74-1.46) or in virological response (OR 0.81; 95% CI 0.46-1.41); differences in mean CD4 T-cell count increase from baseline were at the limit of statistical significance (mean difference 29.8 cells/µL; 95% CI -4.1 to 63.6 cells/µL). In patients changing from EFV, 48% of changes were attributable to toxicity/adverse events, 16% to treatment failure/resistance, 3% to simplification, and 8 and 12%, respectively, to patients' and physicians' decisions; these percentages were 24, 6, 12, 14 and 24%, respectively, in those changing from ATV/r. CONCLUSIONS: ATV/r- and EFV-based regimens meet the requirements of both efficacy and safety for initial combination antiretroviral regimen, which relate to better durability.

Late initiation of HAART among HIV-infected patients in Spain is frequent and related to a higher rate of virological failure but not to immigrant status.

PURPOSE: To determine whether immigrant status is associated with late initiation of highly active antiretroviral treatment (HAART) and/or poor response to antiretrovirals. METHODS: GESIDA 5808 is a multicenter, retrospective cohort study (inclusion period January 2005 through December 2006) of treatment-naïve patients initiating HAART that compares HIV-infected patients who are immigrants with Spanish-born patients. A late starter (LS) was defined as any patient starting HAART with a CD4+ lymphocyte count <200 cells/µL and/or diagnosis of an AIDS-defining illness before or at the start of therapy. The primary endpoint was time to treatment failure (TTF), defined as virological failure (VF), death, opportunistic infection, treatment discontinuation/switch (D/S), or missing patient. Secondary endpoints were time to treatment failure as observed data (TTO; censoring missing patients) and time to virological failure (TVF; censoring missing patients and D/S not due to VF). RESULTS: LS accounted for 56% of the patients. Lower educational and socioeconomic level and intravenous drug use (IVDU) were associated with categorization as LS, but immigrant status was not. Cox regression analysis (hazard ratio [HR]; 95% CI) between LS and non-LS patients showed no differences in TTF (0.97; 0.78-1.20) or TTO (1.18; 0.88-1.58), although it did reveal a difference in TVF (1.97; 1.18-3.29). CD4+ lymphocyte recovery was equivalent for both LS and non-LS patients (159 vs 173). CONCLUSIONS: In our cohort, immigrant status was not shown to be related to late initiation of HAART. Although LS patients did not have a longer TTF for any reason, TVF was significantly shorter. Despite universal free access to HAART in Spain, measures to ensure early diagnosis and treatment of HIV infection are necessary.

Tuberculous hepatic abscess appearing after liver transplantation in a patient with human immunodeficiency virus and hepatitis B and C virus co-infection.

Tuberculosis infection occurs relatively frequently in solid organ transplant recipients, although the occurrence of tuberculous hepatic abscesses is uncommon. Anti-tuberculous therapy has several concerns in transplant recipients, including an increased risk of cellular rejection and potential hepatotoxicity. We present the case of a human immunodeficiency virus-infected liver transplant patient who developed multiple tuberculous liver abscesses. Treatment with isoniazid, ethambutol, pyrazinamide, and moxifloxacin was efficacious, well tolerated, and safe.

Risk of cardiovascular disease in patients with HIV infection undergoing antiretroviral therapy. / Riesgo de enfermedad cardiovascular en pacientes con infección VIH en tratamiento antirretroviral.

BACKGROUND: The increased survival of patients with HIV infection thanks to antiretroviral therapy (ART) is accompanied by a higher rate of cardiovascular disease (CVD). We analysed the prevalence of the cardiovascular risk factors (CRFs) and estimated the risk of CVD in a cohort of patients with HIV in Spain. METHODS: We conducted a cross-sectional, observational study of CRFs in the Spanish VACH cohort of patients with HIV who undergo ART. RESULTS: The study assessed 15,559 patients with HIV (76% men; mean age, 46 years). Some 3.7% had experienced at least 1 CVD event. The prevalence of CRFs was high (hyperlipidaemia, 64%; tobacco use, 47%; arterial hypertension, 22%; and diabetes, 16%). According to the Framingham scale, 10.9% of the patients presented a high CVD risk, and 28.8% presented a moderate risk. Of the patients with a high CVD risk, 49% took protease inhibitors and 43% took abacavir. Fifty-three percent of the patients diagnosed with arterial hypertension took antihypertensive drugs, and 2.6% of the patients with diabetes took antidiabetic agents. CONCLUSIONS: Classical CRFs are common in patients with HIV undergoing ART in Spain, and a large proportion of them have a moderate-high risk of CVD. Therefore, controlling the modifiable CRFs in patients with HIV should be improved, and the use of drugs with a better cardiovascular risk profile should be assessed.

Real World Patient-reported Outcomes in HIV-infected Adults Switching to EVIPLERA®, Because of a Previous Intolerance to cART. PRO-STR Study.

BACKGROUND: To investigate the impact of switching from stable Combined Antiretroviral Therapy (cART) to single-tablet regimen (RPV/FTC/TDF=EVIPLERA® /COMPLERA®) on patient- reported outcomes in HIV-infected adults who cannot tolerate previous cART, in a real-world setting. METHODS: PRO-STR is a 48-week observational, prospective, multicenter study. Presence and magnitude of symptoms (main endpoint), health-related quality-of-life (HRQoL), adherence, satisfaction with treatment and patient preferences were assessed. RESULTS: Three hundred patients with 48-week follow-up, who switched to EVIPLERA® (mean age: 46.6 years; male: 74.0%; 74.7% switched from a non-nucleoside reverse-transcriptase-inhibitor, 25.3% from a protease inhibitor + ritonavir) were included. There was no statistical difference in median CD4+ cell count (baseline: 678.5 cells/mm3; 48-week: 683.0 cells/mm3) neither in virological suppression (≤50 copies/mL) (baseline: 98.3%; 48-week: 95.3%). The most frequent reasons for switching were neuropsychiatric (62.3%), gastrointestinal (19.3%) and biochemical/metabolic (19.3%) events. Only 7.7% of patients permanently discontinued therapy. At 48-week, all outcomes showed an improvement compared to baseline. Overall, there was a significant decrease (pvalue≤ 0.05) in number and magnitude of symptoms, while HRQoL, satisfaction and adherence improved significantly. Most patients prefered EVIPLERA® than previous cART. According to the type of intolerance, HRQoL was improved, but only significantly in patients with neuropsychiatric and gastrointestinal symptoms. Adherence improved significantly in patients with metabolic disturbances and satisfaction with EVIPLERA® was higher in the three groups. CONCLUSION: Switching to EVIPLERA® from non-nucleoside reverse-transcriptase-inhibitor or protease inhibitor-based regimens due to toxicity, improved the presence/magnitude of symptoms, HRQoL, and preference with treatment. EVIPLERA® maintained a virological response, CD4+ cell count and maintained or improved adherence.

Limitations of a simplification antiretroviral strategy for HIV-infected patients with decreasing adherence to a protease inhibitor regimen.

PURPOSE: To determine the long-term efficacy of a simplification strategy in the clinical setting when used to improve adherence. METHOD: Prospective study of 70 patients included in a regimen with ddI plus 3TC plus an NNRTI, after viral suppression with a PI-containing regimen, due to decreasing adherence. Adherence to PI was calculated as the percentage of doses taken last week before inclusion, and patients were stratified as high and low adherence (95% and <95% of doses). RESULTS: Overall, 19 patients (27%) related adherence to PI <95% at inclusion (6 patients [9%], with adherence <80%). Mean adherence improved, with only 8% of patients presenting values <95%. At 104 weeks, 88% of patients on therapy had viral load suppression, but only 43% by ITT analysis. The main cause of therapy change or withdrawal was toxicity or drug interactions (26%). Notably, 16% of patients were lost to follow-up or left therapy, especially in the group of initially low adherent (26% vs. 12%, p = .02). CONCLUSION: The use of a simplification strategy could be associated with long-term high risk of treatment failure, when used to improve adherence in the clinical setting.

Predictors of long-term response to protease inhibitor therapy in a cohort of HIV-infected patients.

OBJECTIVE: To assess the rate of long-term effectiveness and factors associated with response to protease inhibitor therapy in a cohort of HIV-infected patients. DESIGN AND SETTING: Prospective, non-randomized study in a tertiary care centre. PATIENTS: A total of 400 HIV-infected patients who started on protease inhibitor therapy (saquinavir, 28%; ritonavir, 26%; indinavir, 46%) from March 1996 to March 1997. MAIN OUTCOMES MEASURES: Long-term virological and immunological effectiveness were defined as HIV RNA levels below 200 copies/ml and CD4+ cell count increase greater than 100 x 10(6)/l, respectively, after 12 months of therapy. RESULTS: Fifty-seven per cent of patients had a prior AIDS-defining illness, and 91% had received nucleoside analogues for a median time of 28 months. Median CD4+ count was 86 x 10(6) cells/l and HIV RNA level was 4.46 log10 copies/ml. The global rate of virological and immunological effectiveness at 1 year was 45 and 59%, respectively. In a logistic regression analysis, treatment failure was associated with higher baseline HIV load [relative risk (RR), 2.10; P<0.01], prior antiretroviral therapy (RR, 2.07; P<0.01), and use of saquinavir (RR, 1.55; P = 0.03), whereas a reduction of more than 1 log10 in HIV load within the first 3 months on therapy was strongly associated with response (RR, 0.65; P<0.01). There was no strict correlation between virological and immunological effectiveness (r = -0.35; P = 0.01). CONCLUSIONS: Nearly half of the patients maintain undetectable HIV load after 1 year of therapy, although important immunological benefit can be obtained in a greater proportion of patients. These data suggest the use of the most potent antiretroviral therapy in pretreated patients with high HIV load, and the capacity of initial virological decline to predict the long-term outcome.

Phenotypic testing predicts virological response in successive protease inhibitor-based regimens.

OBJECTIVE: To evaluate the importance of the number of active drugs, as determined by phenotypic resistance testing, in achieving virological response in successive salvage regimens. DESIGN: Phenotypic study of 57 plasma samples corresponding to 24 patients who had sequentially received three protease inhibitor-containing regimens. Phenotypic susceptibility to a drug (active drug) was defined as less than a four-fold-increase in the IC50 in comparison with the wild type. MAIN OUTCOME MEASURE: Virological response according to the number of active drugs (three versus two or fewer), HIV load, length of antiretroviral exposure, and line of protease inhibitor-based therapy (first, second and third regimen). RESULTS: Before the first protease inhibitor-based therapy, the median time on antiretroviral treatment was 42 months, and before the second and third protease inhibitor-salvage regimens it was 10 and 8 months, respectively. The number of patients receiving three active drugs simultaneously was 24, 35 and 31% in each line of therapy. At week 12, a close correlation was found between the presence of three active drugs in the antiretroviral regimen and the rate of virological response, in comparison with those patients receiving two or fewer active drugs [76 versus 45%, relative risk (RR), 1.7; 95% confidence interval (CI) 1.1-2.6; P = 0.028]. In a multivariate analysis, the use of two or fewer active drugs was an independent predictor of lack of response, regardless of HIV load, length of previous antiretroviral exposure and line of salvage therapy (RR, 4.5; 95%CI, 1.1-18.3; P = 0.03). Of note, a higher rate of response was observed in patients receiving the first protease inhibitor-containing regimen in comparison with those in subsequent protease inhibitor-based salvage regimens (83 versus 50 versus 28%, P < 0.01), even when only those patients receiving three active drugs were included (100 versus 71 versus 60%). CONCLUSIONS: This data confirm the usefulness of phenotypic testing in guiding antiretroviral therapy in heavily pretreated patients. The number of active drugs and the line of salvage therapy are independent predictors of virological response, regardless of HIV load and the length of antiretroviral exposure.

Patients failing saquinavir therapy require an early change to indinavir before HIV-1 viral load reaches high levels.

Sequential use of antiretroviral therapy with protease inhibitors (PI) is frequently prescribed owing to failure or intolerance of the first selected agent. Controversial data exist about the virological and immunological outcome of patients in whom a change to a second PI regimen is needed. A prospective study of 113 HIV-positive patients (male, 84%; mean age 36 years; previous AIDS-defining event, 35%; previous antiretroviral therapy with nucleoside analogues, 94%) who started a saquinavir-containing regimen between March 1996 and March 1997 and had to change to indinavir (n = 79) owing to intolerance, failure or medical criteria was performed. At the time of the switch, median CD4 cell count was 221 cells/mm3 and the HIV RNA level was 3.98 log10 copies/ml. The rate of viral suppression (HIV RNA levels below 200 copies/ml) was 40% at 3 months and 28% at month 6 after indinavir was instituted. In a logistic regression analysis, only the baseline viral load [relative risk (RR), 2.85; 95% confidence interval (CI), 1.31-6.05; P = 0.007] was statistically associated with the lack of viral suppression on indinavir. Although there are not sufficient data about the best therapeutic option if a change in PI-containing regimens therapy is considered, this study supports the recommendation of an early change of the PI-containing regimens, before the HIV-1 viral load reaches high levels.

Percentage of adherence correlates with the risk of protease inhibitor (PI) treatment failure in HIV-infected patients.

OBJECTIVES: To determine the effect of adherence on the rate of protease inhibitor (PI) treatment failure among human immunodeficiency virus (HIV)-infected patients. METHODS: A prospective study of a cohort of 282 patients who initiated PI therapy from March 1996 to December 1997. Adherence was quantified as the percentage of prescribed doses reportedly taken and treatment failure was defined as HIV RNA levels above 200 copies/ml after 1 year on therapy. RESULTS: Overall, 190 patients (67%) missed prescribed doses. However, mean percentage of doses taken was 91% (range, 21-100%). Demographic, virological and immunological characteristics could not predict adherence outcomes. The causes of non-adherence included intolerance or side effects (35%), complexity of treatment (23%), or recurrence in active drug abuse (17%), whereas abandonment owing to HIV-related disease was uncommon (6%). A degree of adherence above 90% correlated significantly with viral suppression [relative risk (RR) 1.69; 95% confidence interval (CI) 1.1-2.56; P<0.01]. In a multivariate analysis, a lower degree of adherence (RR, 0.96; P=0.006), a higher HIV viral load (RR, 2.03; P=0.0001), prior antiretroviral therapy (RR, 2.5; P=0.01), and use of saquinavir-hard gel capsules (saquinavir-HGC) (RR, 1.77; P=0.03) were strongly associated with treatment failure. CONCLUSION: The percentage of adherence and initial HIV viral load are the most important determinants of virological response to PI therapy and non-adherence is related to treatment-related factors in the majority of cases.

Effectiveness and pitfalls of initial highly active antiretroviral therapy in HIV-infected patients in routine clinical practice.

OBJECTIVE: To assess the long-term effectiveness of and factors associated with response to protease inhibitors (PIs) in a cohort of treatment-naive HIV-infected patients. DESIGN AND SETTING: Prospective study in a tertiary care centre. SUBJECTS: A total of 207 treatment-naive patients starting PIs from March 1996 to May 1998. MAIN OUTCOME MEASURES: Clinical, virological and immunological outcomes, and adherence to therapy after 12 months. RESULTS: Baseline median CD4 cell count and viral load were 160 cells/mm3 and 5 log10 copies/ml, respectively. After 48 weeks, 168 patients (81%) reached plasma HIV-RNA levels below 400 copies/ml, and the mean increase in CD4 cell count was 196 cells/mm3. Clinical events were observed in 29 patients (14%) after a median time of 100 days on therapy, yet mortality was extremely low (0.9%). By multivariate analysis, adherence over 90% [relative risk (RR), 16.66; 95% confidence interval (CI), 5.26-50; P=0.00001] and AIDS diagnosis at baseline (RR 0.35; 95% CI, 0.14-0.90; P=0.02) were the strongest predictors for virological suppression. An immunological recovery over 100 cells/mm3 was significantly associated with an initial virological response (RR 2.94; 95% CI, 1.31-6.66; P=0.009) and adherence over 90% (RR 3.44; 95% CI, 1.61-7.69; P=0.005). There were high rates of change with the first PI (40%), mostly due to adverse events (51%), but it did not compromise long-term effectiveness. CONCLUSIONS: Initial PI treatment in the clinical setting is able to reach equally good outcomes as those found in controlled trials. Changes in therapy due to toxicity do not compromise a successful outcome, which clearly depends on an adequate adherence to therapy.

Efficacy, tolerance, and pharmacokinetics of the combination of stavudine, nevirapine, nelfinavir, and saquinavir as salvage regimen after ritonavir or indinavir failure.

The high rate of protease inhibitor treatment failure in clinical cohorts makes it necessary to define novel salvage therapies. In a prospective study of 31 HIV-infected patients included in a salvage regimen with stavudine, nevirapine, nelfinavir, and saquinavir, viral load decreased a median of 1.65 log(10) and 1.95 log(10) after 6 and 12 months of treatment, respectively, and 35 and 56% of patients had an HIV RNA level below 50 copies/ml at the same time points. At baseline, the mean number of mutations in the protease gene was 10 (2-19), and the V82A and L90M mutations were present in 54 and 21% of patients. The presence of the V82A mutation did not affect significantly the rate of response (36 vs. 38%), whereas the L90M mutation was associated with treatment failure (0 vs. 43%). Plasma trough levels of nelfinavir (NFV) and saquinavir (SQV), in a twice daily dosing regimen, were above the protein-corrected IC(95) in most patients despite the addition of an enzymatic inducer such as nevirapine, and peak levels were 2- and 5-fold increased with respect to standard doses. However, pharmacokinetics of saquinavir-hard gel capsule (SQV-hgc) did not improve significantly in the three times daily dosing regimen. In conclusion, the combination of stavudine, nevirapine, nelfinavir, and saquinavir increased plasma drug levels and produced an adequate virological response in patients who had failed indinavir or ritonavir therapy. This degree of response is not significantly decreased in the presence of genotypic mutations associated with indinavir/ritonavir (IDV/RTV) resistance.

Phenotypic cross-resistance to nelfinavir: the role of prior antiretroviral therapy and the number of mutations in the protease gene.

Cross-resistance to nelfinavir (NFV) is observed in patients failing protease inhibitor (PI)-containing therapies. We performed a study with 111 patients who started an NFV-based salvage regimen after failing PI-based therapy to evaluate genotypic changes and to identify factors associated with resistance to NFV. Genotypic and phenotypic resistance data at entry (111 and 51 samples) and after NFV failure (74 and 31 samples) were available. Median CD4(+) cell count was 208 x 10(6)/liter, HIV RNA level was 4.6 log(10) copies/ml, and median number of mutations in the protease was 9. At baseline, 51 and 14% of viral isolates showed high or intermediate phenotypic resistance to NFV. Phenotypic data correlated with virological outcome, reaching undetectability at the third month in 40, 14, and 0% of those patients with susceptible, intermediate, or resistant viral isolates, respectively. Phenotypic resistance to NFV was associated with the presence of the L90M mutation: 46% for resistant vs. 6% in susceptible strains. The number of mutations in the protease correlated with the fold-increase in the IC(50)-NFV. The D30N mutation was detected in only 1 of 74 patients who failed. In a logistic regression analysis, the number of mutations in the protease was associated with NFV cross-resistance (RR, 2.09 per each additional mutation; 95% CI 1.23-3.55; p < 0.01). In conclusion, phenotypic cross-resistance to NFV for PI-experienced patients can be predicted by the number of mutations in the protease. The L90M mutation is significantly associated with the subsequent failure of NFV-containing regimens. The presence of the D30N mutation was rare and not useful in identifying NFV-resistant isolates.

Central venous catheter infections in AIDS patients receiving daily home therapy for cytomegalovirus disease.

We studied the infection rate of long-term intravenous access used for daily home treatment of cytomegalovirus (CMV) disease in 61 AIDS patients who had 75 central venous catheters implanted for antiviral maintenance therapy between February 1989 and December 1994. In 39 patients (64%) the risk factor for AIDS was intravenous drug abuse. Sixty-three catheters were Hickman type and 12 were totally implanted ports. The cumulative follow-up time was 19000 catheter-days (52 patient-years), with median duration of placement of 249 days. The infection rate was 0.22 infections per 100 catheter days. The probability of remaining free of catheter-related sepsis was 58% at 6 months. In 25 cases (61%) antimicrobial therapy without catheter removal was successful. Three patients died because of a catheter-related infection (mortality rate 7.3%). Infection-free survival time was not related to the risk factor for AIDS (p = 0.44) or type of device (p = 0.41). The total infection rate in these patients receiving daily home maintenance therapy for CMV disease through a long-term catheter was similar to that in other AIDS patients receiving weekly treatment in hospital facilities.

A clinical study of the combination of 100 mg ritonavir plus 800 mg indinavir as salvage therapy: influence of increased plasma drug levels in the rate of response.

PURPOSE: The purpose of our study was to evaluate the efficacy of indinavir (IDV) in a twice daily dosing regimen with coadministration of 100 mg ritonavir (RTV) and to explore the influence of plasma drug levels in the rate of virologic response. METHOD: We performed a prospective study of 59 patients who switched to a salvage regimen with two nucleoside analogs plus the combination of 100 mg RTV plus 800 mg IDV twice daily. Pharmacokinetics of IDV and RTV were assessed in 11 patients. RESULTS: Previous antiretroviral exposure was 44 months, and 78% and 39% of patients had previously failed regimens with either IDV or RTV. Median CD4 count was 248 x 10(6)/L and HIV load was 3.9 log(10) copies/mL. The median number of mutations in the protease gene was 9 (3-14), predominantly at residues 82 (53%), 90 (42%), and 46 (32%). After 24 weeks, 61% of patients had a viral load decrease greater than 1 log(10), and 38% had a viral load below 50 copies/mL. Nephrolitiasis, hematuria, or flank pain was observed in 13 patients (22%), leading to withdrawal in six cases (10%). IDV trough levels were well above the IC(95) (median 1.75 mg/L, interquartile range 1.07-2.57), but RTV trough levels were below the IC(95) in 88% of patients. There was a close correlation between higher peak levels of IDV, virological response, and renal toxicity. CONCLUSION: RTV/IDV 100/800 mg in a twice daily dosing regimen is associated with a significant virological response in patients with antiretroviral treatment failure. The correlation between plasma drug levels, toxicity, and response suggests the usefulness of individualized drug monitoring.