Pancreatic insufficiency in patients with HIV infection: role of didanosine questioned.

OBJECTIVES: The aim of the study was to identify possible causes of pancreatic insufficiency in patients with HIV infection. METHODS: A retrospective analysis of 233 HIV-positive patients for whom faecal elastase measurement was available was performed to investigate potential associations with core demographic data, HIV infection characteristics, degree of immunosuppresion, exposure to antiretroviral therapy (ART), alcohol misuse, diabetes, hepatitis C virus (HCV) infection, triglyceride and cholesterol levels and symptomatology. The response to pancreatic enzyme replacement for patients with evidence of insufficiency was also evaluated. RESULTS: Of 233 patients, 104 (45%) had evidence of pancreatic exocrine insufficiency (faecal elastase < 200 mcg/g). A positive association with exocrine pancreatic insufficiency was found for HCV infection (P = 0.007), previous or current HCV treatment (P = 0.003), alcohol misuse history (P = 0.006) and the presence of steatorrhoea (P = 0.03). There was no demonstrated association between exocrine pancreatic insufficiency and didanosine (ddI) exposure (P = 0.43) or stavudine (d4T) exposure (P = 0.62). Seventy-seven per cent of patients who were treated with pancreatic enzymatic supplementation reported a subjective improvement in symptoms. CONCLUSIONS: Faecal elastase sampling should form part of the routine work-up for HIV-positive patients with chronic diarrhoea even in the absence of 'traditional' risk factors such as ddI exposure. In particular, if the patient has steatorrhoea, a history of alcohol exposure or their HCV serology is positive, they should be considered for investigation. Treatment with pancreatic enzyme supplementation appears to be effective in the treatment of chronic diarrhoea caused by pancreatic insufficiency in the majority of patients.

British HIV Association and Children's HIV Association position statement on infant feeding in the UK 2011.

To prevent the transmission of HIV infection during the postpartum period, the British HIV Association and Children's HIV Association (BHIVA/CHIVA) continue to recommend the complete avoidance of breast feeding for infants born to HIV-infected mothers, regardless of maternal disease status, viral load or treatment.

Switching from twice-daily abacavir and lamivudine to the once-daily fixed-dose combination tablet of abacavir and lamivudine improves patient adherence and satisfaction with therapy.

BACKGROUND: Patients prefer fewer pills and once-daily (qd) dosing without food restrictions. We assessed the impact on adherence [by Medication Event Monitoring System (MEMS) cap monitoring] of switching from abacavir (ABC) and lamivudine (3TC) twice daily (bid) to ABC/3TC fixed-dose formulation (FDC, Kivexa) qd to achieve a qd regimen. METHODS: A randomized, open-label, 8-week study comparing adherence, efficacy and safety of immediate vs. delayed switching from ABC/3TC to FDC qd. RESULTS: Ninety-four patients were dosed. Significantly improved adherence was observed at week 4 with qd ABC/3TC across all three adherence variables: taking compliance 99.2% (90.7-100%) vs. 96.6% (60.0-100%) (P=0.017); dosing compliance 97.1% (64.3-100%) vs. 91.9% (33.3-100%) (P=0.016); and timing compliance 95.5% (53.8-100%) vs. 86.3% (4.3-100%) (P=0.006). Treatment satisfaction increased significantly at week 4 with ABC/3TC qd [92% (82-99%) vs. 85% (75-93%) (P=0.004)]. Two patients were withdrawn from the study because of intolerance to ABC/3TC. CONCLUSIONS: Switching from ABC and 3TC bid to ABC/3TC FDC qd significantly improved adherence by MEMS cap monitoring at week 4 and improved patient satisfaction with therapy. The results remain to be confirmed over a longer follow-up. Use of qd regimens supports adherence and improves treatment satisfaction relative to bid regimens.

Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma.

PURPOSE: A proportion of patients with HIV infection who subsequently receive highly active antiretroviral therapy (HAART) exhibit a deterioration in their clinical status, despite control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens. PATIENTS AND METHODS: From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively. RESULTS: After commencing HAART, ten patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = .03), KS-associated edema (P = .01), and therapy with both protease inhibitors and non-nucleosides together (P = .03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS. CONCLUSION: We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.

Clinically significant azole cross-resistance in Candida isolates from HIV-positive patients with oral candidosis.

OBJECTIVES: To determine the proportion of fluconazole-resistant Candida albicans isolates that have clinically significant cross-resistance to itraconazole or ketoconazole, that is sufficient to result in failure of these agents at their standard doses (200 and 400 mg daily for 7 days, respectively). METHODS: Seven hundred C. albicans isolates from HIV-positive patients with oral candidosis underwent susceptibility testing using a relative growth method, for which cut-off values corresponding to clinical drug failure have been established. RESULTS: A total of 431 isolates were fully azole-susceptible and three main resistance patterns were detected: isolates resistant to fluconazole alone (n = 100); isolates resistant to fluconazole and ketoconazole but susceptible to itraconazole (n = 94); and isolates resistant to all three drugs (n = 50). No isolates were consistently resistant to ketoconazole without being fluconazole-resistant, and no itraconazole resistance was detected without ketoconazole resistance. Resistance to fluconazole alone was more common in specimens obtained soon after first clinical fluconazole failure, whereas specimens from patients with a longer history of fluconazole-unresponsive candidosis were more likely to be infected with cross-resistant isolates. Median days of prior azole exposure and cumulative fluconazole dose were significantly less for those with isolates resistant to fluconazole alone than for those with ketoconazole cross-resistant isolates, who had received less azole therapy and smaller cumulative fluconazole doses than those with isolates cross-resistant to all three drugs (although not statistically significant). After the diagnosis of fluconazole-unresponsive candidosis, increasing cumulative doses of itraconazole solution were associated with increasing likelihood of cross-resistance. CONCLUSIONS: Clinically significant cross-resistance to other azoles may occur in fluconazole-resistant isolates of C. albicans, although initially most isolates are not cross-resistant and the detection of cross-resistant isolates is associated with a history of greater prior azole exposure. Patients who have been treated for fluconazole-resistant candidosis for longer and with greater cumulative doses of itraconazole solution tend to become infected with increasingly cross-resistant isolates of C. albicans.

Itraconazole cyclodextrin solution: the role of in vitro susceptibility testing in predicting successful treatment of HIV-related fluconazole-resistant and fluconazole-susceptible oral candidosis.

OBJECTIVES: This study assessed the ability of in vitro susceptibility testing of clinical Candida isolates to predict in vivo response to itraconazole cyclodextrin solution. METHODS: One hundred specimens were obtained from HIV-positive patients with oral thrush, of which 72 speciments were from patients who were clinically unresponsive to fluconazole at standard doses and had fluconazole-resistant isolates in vitro. Susceptibility to itraconazole was assessed by measuring the relative growth of an isolate in liquid medium containing a single concentration of itraconazole and then expressing growth in itraconazole as a percentage of growth in antifungal-free medium. RESULTS AND CONCLUSIONS: Where specimens yielded only one isolate, a cut-off relative growth in itraconazole of 68% discriminated between isolates from patients failing to respond clinically to itraconazole solution and those from patients successfully treated with the preparation (specificity 100%; sensitivity 88%). The presence of mixed infection reduced the predictive accuracy of the test. Only 30% of fluconazole-resistant isolates were cross-resistant to itraconazole. No isolates were resistant to itraconazole but susceptible to fluconazole. Non-response to itraconazole solution was attributed to resistant yeast infection in the majority of cases, and this susceptibility method accurately identified specimens from patients unlikely to respond to the drug.

The metabolic response to opportunistic infections in AIDS.

OBJECTIVE: The metabolic response to AIDS-defining opportunistic infections was examined to provide a logical basis for the management of associated weight loss. DESIGN: A prospective study of metabolism in AIDS. SETTING: HIV outpatients' department and wards at the Chelsea and Westminster Hospital, London. PATIENTS: Ten asymptomatic Centers for Disease Control and Prevention stage II HIV-seropositive control subjects and 36 HIV-seropositive patients with a single newly diagnosed and untreated opportunistic infection [10 with microsporidial or cryptosporidial diarrhoea, 10 with Pneumocystis carinii pneumonia, nine with cytomegalovirus enteritis and seven with systemic Mycobacterium avium-intracellulare]. MAIN OUTCOME MEASUREMENTS: Subjects had measurements of resting energy expenditure using indirect calorimetry and of body composition using dual energy X-ray absorptiometry. RESULTS: Subjects with protozoal diarrhoea had a decreased resting energy expenditure (P < 0.05) and decreased body fat (P < 0.01). Subjects with P. carinii pneumonia had an elevated resting energy expenditure (P < 0.05). Subjects with systemic M. avium-intracellulare had an elevated resting energy expenditure (P < 0.05) and decreased skeletal muscle mass (P < 0.05). Subjects with cytomegalovirus enteritis had a non-significant elevation of resting energy expenditure with a non-significant loss of both fat and lean tissue. CONCLUSION: Subjects with protozoal diarrhoea show a starvation response to infection and subjects with systemic M. avium-intracellulare show a cachectic response. Since there is a variation in the metabolic response to opportunistic infection in AIDS patients, nutritional management should be directed according to the specific cause.

Cessation of secondary prophylaxis in patients with cryptococcosis.

Cryptococcal disease in HIV-positive individuals is usually a consequence of advanced immunosuppression. Treatment consists of long period of induction therapy followed by long-term secondary prophylaxis, usually with fluconazole. The introduction of highly active antiretroviral therapy has resulted in improvements in immunological function such that the cessation of primary and secondary prophylaxis against several opportunistic infections has become possible. We report our experience of the cessation of secondary antifungal prophylaxis in patients responding to highly active antiretroviral therapy.

The value of barium enema and colonoscopy in patients infected with HIV.

Double contrast barium enema (DCBE) and colonoscopy were prospectively compared with rigid sigmoidoscopy, rectal biopsy and microbiological examination in the analysis of stool specimens in 58 HIV-1-infected patients with diarrhoea (more than three liquid motions/day for greater than 1 month). In 26 patients no cause for the diarrhoea was found. In 17 patients the cause of diarrhoea was microbiological, and in 19 rectal histology provided a specific diagnosis. In all these patients sigmoidoscopic appearances were abnormal except in those with Cryptosporidium alone. Colonoscopy provided additional information in only one individual, with cytomegalovirus ulcers of the transverse colon. DCBE was abnormal in only seven cases (cytomegalovirus in three, Kaposi's sarcoma in two, Giardia lamblia in two) and in no case provided additional information. A combination of stool microbiology and rectal histology gave a sensitivity of 97% with a positive predictive value of 100%. The sensitivities of DCBE and colonoscopy with histology were low (16 and 62%, respectively) although the specificity for each test was high, with high positive predictive values. We conclude that neither barium enema nor colonoscopy add usefully to rigid sigmoidoscopic biopsy and stool microscopy in HIV-positive patients with diarrhoea.

Investigation of upper gastrointestinal symptoms in patients with AIDS.

Double contrast barium radiology and upper gastrointestinal endoscopy were compared prospectively on 45 occasions in patients infected with HIV who presented with upper gastrointestinal symptoms. In 40 cases, a definite pathological diagnosis was reached and in four cases no organic basis for symptoms could be found. A correct and complete diagnosis was made on visual endoscopic criteria in 43 cases (95.5%) but in only 14 cases (31.1%) from barium studies alone. Radiology showed no abnormality in 22 cases where pathological changes were documented (oesophageal candidiasis in 21 cases). Where pathological confirmation of diagnosis existed (40 cases), endoscopy (without pathological support) had a sensitivity of 97.5% and a specificity of 100% compared with the sensitivity and specificity of 25 and 100% for barium studies. The difference between the sensitivities of the two methods was highly significant (P less than 0.005). The combination of oral candidiasis and upper gastrointestinal symptoms without dysphagia or weight loss was so strongly associated with uncomplicated oesophageal candidiasis (negative predictive value 93%; P less than 0.025), that this is supported as a basis for therapy without the need for further investigation, although if upper gastrointestinal investigation is required, endoscopy should be the method of choice.

Treatment with corticosteroids--a risk factor for the development of clinical cytomegalovirus disease in AIDS.

OBJECTIVE: To assess the frequency with which HIV-seropositive patients treated with corticosteroids develop cytomegalovirus (CMV) disease. DESIGN: Retrospective case-controlled study. METHODS: All 130 patients receiving systemic corticosteroids over a 20-month period at the HIV Unit, Westminster Hospital, London, UK were reviewed for the development of clinical CMV disease within 28 days. The incidence of CMV disease in this group was compared with that in a cohort admitted during the same period, which was matched for admission diagnosis, HIV risk group, antiretroviral therapy and CD4 lymphocyte subset count (+/- 20%) at admission. RESULTS: Eleven of the 130 patients given corticosteroids developed CMV disease within 28 days, compared with two patients in the case-controlled cohort. All patients who developed CMV disease had a CD4 count < 50 x 10(6)/l on admission. CONCLUSION: The use of corticosteroids in patients with advanced immunosuppression due to HIV infection should be reviewed carefully in view of the possible increased incidence of CMV disease.

Pseudomonas septicaemia associated with HIV.

Between July 1985 and January 1990, pseudomonas scepticaemia occurred in 19 out of 584 patients with AIDS attending the Westminster and St Stephen's AIDS Unit, London, UK. Ten of these 19 were being treated for active cytomegalovirus infection. Fourteen of the 19 patients had a central venous catheter in situ, which was the source of infection in 11. Seven patients died. Mortality was significantly greater in those patients infected with Pseudomonas aeruginosa, in those patients whose source of infection was not the central venous line, and in those patients whose central line was not removed.

The role of azoles in the treatment and prophylaxis of cryptococcal disease in HIV infection.

OBJECTIVE: To assess the role of azole therapy in the treatment and prophylaxis of cryptococcosis in HIV-seropositive individuals. STUDY DESIGN: Retrospective case review. SETTING: A dedicated HIV unit in London, UK. PATIENTS: Fifty individuals with a positive cryptococcal antigen or culture from any site between 1 January 1985 and 31 December 1992. RESULTS: Thirty-eight patients initially presented with meningitis and 12 with alternative disease, five of whom subsequently developed meningeal disease. The 12 patients who presented without meningitis received chronic suppressive therapy after the diagnosis of cryptococcal disease. Two patients receiving itraconazole developed meningitis as did three out of four treated with 200 mg fluconazole daily, but none of the six receiving 400 mg fluconazole daily. Treatment of cryptococcal meningitis was successful in 17 of the 19 patients given fluconazole but only three of the six receiving itraconazole. Following successful treatment of meningitis five out of seven patients given itraconazole and five out of seven given 200 mg fluconazole daily relapsed compared with three out of 25 receiving 400 mg fluconazole daily. CONCLUSION: Fluconazole is an effective treatment for cryptococcal meningitis. For prophylaxis following meningitis, a dose of 400 mg fluconazole is the preferred treatment; lower doses are associated with a higher relapse rate.

Reversible renal failure caused by a microsporidian infection.

OBJECTIVE: To report a case of renal failure associated with microsporidian infection in an HIV-seropositive patient. DESIGN: Case report. SETTING: Chelsea and Westminster Hospital, London, England, UK. PATIENT: An HIV-seropositive patient presented febrile with abdominal pain who developed renal failure. Renal biopsy and urinalysis showed infection with a microsporidian of the genus Encephalitozoon. INTERVENTION: Treatment with albendazole (400 mg) twice daily was associated with disappearance of infection from the urine, clinical improvement and return of renal function virtually to normal. CONCLUSION: HIV-seropositive individuals with renal failure should have urine screened for microsporidia. The administration of albendazole in such cases may reverse renal failure.

Faecal tumour necrosis factor-alpha in individuals with HIV-related diarrhoea.

OBJECTIVE: HIV-related gastrointestinal infection is associated with diarrhoea, weight loss, mucosal inflammation and increased intestinal permeability. As tumour necrosis factor (TNF)-alpha may mediate these features this cytokine was measured in the faeces of HIV-seropositive individuals with diarrhoea to assess its role in the pathogenesis of HIV-related gastrointestinal disease and the association with specific intestinal pathogens. DESIGN: Prospective study. METHODS: Two hundred and four HIV-seropositive individuals provided stool samples that were analysed for faecal TNF-alpha (FTNF-alpha) using a standard sandwich enzyme-linked immunosorbent assay. RESULTS: Stool from patients with bacterial, cytomegalovirus (CMV) and microsporidial diarrhoea had significantly elevated FTNF-alpha compared with those who had pathogen-negative diarrhoea (P < 0.05). FTNF-alpha was not raised in cryptosporidiosis, pathogen-negative or solid stool. In subjects with diarrhoea of more than 2 weeks duration and three stool samples negative for enteric pathogens, FTNF-alpha greater than 15 U/ml has a sensitivity of 88% and a specificity of 66% for the diagnosis of diarrhoea-related CMV enteritis. CONCLUSION: TNF-alpha production may have a role in the pathogenesis of bacterial, microsporidial and CMV-related diarrhoea in HIV-seropositive individuals. Thus, anti-TNF-alpha agents may have a therapeutic role in the management of these conditions. FTNF-alpha greater than 15 U/ml in apparently pathogen-negative diarrhoea may suggest endoscopic gastrointestinal biopsy to diagnose CMV enteritis.

Itraconazole versus ketaconazole in the treatment of oral and oesophageal candidosis in patients infected with HIV.

To determine the efficacy and toxicity of two systemically active antifungal agents in the treatment of buccal and oesophageal candidiasis 111 HIV-infected patients with microscopically-confirmed candidiasis were randomized to receive either 200 mg itraconazole once a day or 200 mg ketoconazole twice a day for 28 days in a double blind study. After 1 week of treatment, 75 and 82% of the patients on itraconazole and ketoconazole, respectively, had responded clinically. After 4 weeks of treatment, this had risen to 93% in each group. One patient discontinued itraconozole because of toxicity (rash), five patients discontinued ketaconazole (two nausea, two hepatotoxicity and one rash). Despite successful clinical and mycological clearance, 80% patients had a further episode of candidosis within the next 3 months.

Salmonella, Campylobacter and Shigella in HIV-seropositive patients.

OBJECTIVE: To study the incidence, clinical features, treatment and outcome of patients with Salmonella, Shigella or Campylobacter infection. DESIGN: Retrospective analysis. SETTING: Two dedicated HIV units within a London teaching hospital. METHODS: All patients with Salmonella, Shigella or Campylobacter infection were reviewed retrospectively by correlating the records of the gastrointestinal and microbiology departments with the computerized records of all HIV-positive patients attending the two clinics. RESULTS: Between July 1985 and June 1991, 56 episodes of Salmonella, 37 of Campylobacter and eight of Shigella infection were documented in HIV-seropositive patients. Shigella was most likely to occur early in HIV disease, whilst patients with Campylobacter or Salmonella were more likely to have had a previous AIDS diagnosis. Septicaemica was most common in patients with Salmonella and was especially likely to occur in individuals with an AIDS diagnosis. Relapse of infection was common in patients with Salmonella, especially in those with low CD4 lymphocyte counts, those with an initial septicaemic illness and those not treated with ciprofloxacin. CONCLUSIONS: Patients with Salmonella who have low CD4 lymphocytes counts and/or a septicaemic illness should be considered for life-long secondary prophylaxis with ciprofloxacin because of the high rate of relapse observed. Administration of zidovudine or cotrimoxazole as prophylaxis against Pneumocystis carinii pneumonia may prevent the development of salmonellosis: significantly fewer patients with this infection were taking these drugs than patients with Campylobacter.

Eflornithine versus cotrimoxazole in the treatment of Pneumocystis carinii pneumonia in AIDS patients.

OBJECTIVES: To compare cotrimoxazole and eflornithine as primary treatment for first-episode Pneumocystis carinii pneumonia (PCP). DESIGN: Prospective open-labelled study. METHODS: Patients were randomized to eflornithine (400 mg/kg daily, as a continuous intravenous infusion) or cotrimoxazole (3.84 g twice daily, intravenously) for 14 days. RESULTS: Only 39% of patients treated with eflornithine (20 out of 51) and 40% of those given cotrimoxazole (nine out of 47) successfully completed therapy. Although 12 out of the 36 patients with confirmed PCP were treated successfully with eflornithine, significantly more patients were withdrawn from the eflornithine group because of therapy failure (25 out of 51 versus 10 out of 47, P = 0.007). This significant difference persisted in patients in whom a diagnosis of PCP was confirmed histologically (19 out of 33 versus seven out of 27, P = 0.03). Significantly more patients were withdrawn from cotrimoxazole because of serious drug-related side-effects (38 versus 12%, P = 0.005). CONCLUSIONS: Eflornithine (400 mg/kg daily) is less effective than cotrimoxazole (7.68 g daily) as treatment for first-episode PCP. Eflornithine does have activity against P. carinii in humans.

Dietary advice with or without pravastatin for the management of hypercholesterolaemia associated with protease inhibitor therapy.

BACKGROUND: Therapy with a HIV protease inhibitor is associated with elevations in cholesterol and triglycerides. HMG-CoA reductase inhibitors ('statins') are the established therapy for persons with primary hypercholesterolaemia. Because of drug interactions, pravastatin may represent the preferred choice in those taking HIV protease inhibitors. DESIGN: A randomized, open-label comparative 24 week trial of dietary advice alone or with pravastatin in 31 male patients established on protease inhibitor-based regimens for greater than 12 weeks with viral load < 500 copies/ml and cholesterol > 6.5 mmol/l. RESULTS: There were no significant clinical or laboratory events and no patient discontinuation secondary to adverse effects. Viral rebound did not occur. Relative to baseline, total cholesterol at week 24 fell significantly in the pravastatin (1.2 mmol/l; 17.3%) (P < 0.05) but not in the dietary advice (0.3 mmol/l; 4%) group. The difference between the two groups approached significance at week 24 (P = 0.051). This fall was accounted for entirely by a reduction in low density lipoprotein [calculated change 1.24 mmol/l (19%) and 0.07 mmol (5.5%) in pravastatin and dietary advice groups, respectively] as high density lipoprotein rose non-significantly by 0.6 mmol/l in both groups. Weight, basal metabolic rate, fasting glucose and triglycerides did not change significantly in either group. CONCLUSIONS: Dietary advice plus pravastatin significantly reduced total cholesterol in HIV-positive individuals taking protease inhibitors, without significant adverse effects. The inclusion of pravastatin substantially increases the magnitude of the change, which is comparable with changes achieved in endogenous hyperlipidaemia.

Increasing survival in AIDS patients with cytomegalovirus retinitis treated with combination antiretroviral therapy including HIV protease inhibitors.

OBJECTIVE: To assess the effect of combination antiretroviral therapy including HIV protease inhibitors on the survival of patients with cytomegalovirus retinitis (CMVR). DESIGN AND PARTICIPANTS: A longitudinal study of patients with CMVR diagnosed between October 1992 and May 1996 and followed to May 1997. SETTING: UK National Health Service specialist HIV medicine department. OUTCOME MEASURE: Time to death from first diagnosis of CMVR. Data were censored on 31 May 1997. RESULTS: Data were available on 147 patients with CMVR. Median survival of CMVR patients before December 1995 was 256 days [95% confidence interval (CI), 197-315]. Following the introduction of protease inhibitors in December 1995 this rose to 555 days (95% CI, 351-759). By 31 May 1996 median survival for the entire group of patients alive with CMVR had risen to 720 days (95% CI, 551-889). The mean survival after CMVR diagnosis was 224 days (n=89; 95% CI, 186-261; 1-year survival, 16%) in those who took no further antiretroviral therapy, 353 days in those who took nucleoside reverse transcriptase inhibitors but no protease inhibitors (n=34; 95% CI, 289-418; 1 -year survival, 50%), and 914 days in those who took a protease inhibitor (n=24; 95% CI, 768-1059; 1-year survival, 83%; P < 0.0001). Multivariate analysis showed that the strongest independent predictor of improved survival was having ever received a protease inhibitor after CMVR (relative risk of death, 0.063; 95% CI, 0.027-0.149; P < 0.0001). CONCLUSIONS: The use of HIV protease inhibitors in combination antiretroviral therapy has been associated with a marked increase in the survival of patients with CMVR.