Differential CD4 T-cell response in HIV-1-infected patients using protease inhibitor-based or nevirapine-based highly active antiretroviral therapy

Objectives

To study the dynamics of CD4 T‐lymphocyte counts (CD4 counts) after the initiation of either protease inhibitor (PI)‐based or nevirapine (NVP)‐based first‐line highly active antiretroviral therapy (HAART).

Design and methods

A retrospective cohort study of 1029 HIV‐infected antiretroviral therapy‐naive patients initiating either PI‐based or NVP‐based HAART was carried out. Patients were censored as soon as they experienced virological failure, or changed their original antiretroviral regimen for any reason.

Results

In total, 920 and 109 patients initiated PI‐ and NVP‐based HAART, respectively. The patients in the PI group more often had AIDS (15 vs. 6% in the NVP group), had a lower median baseline CD4 count (234 vs. 250 cells/μL in the NVP group) and had higher median baseline plasma HIV‐1 RNA levels (pVL) (5.0 vs. 4.7 log₁₀ HIV‐1 RNA copies/mL in the NVP group). After 96 weeks of follow‐up, the mean increase from baseline in CD4 count, adjusted for baseline CD4 count, age, gender and baseline pVL, was 310 cells/μL in the PI group and 212 cells/μL in the NVP group (P=0.003). This difference was mainly attributable to the patients in the NVP group initiating HAART with a baseline CD4 count below 200 cells/μL. There were no differences between the PI and NVP groups with respect to the change in the number of CD4 cells as a proportion of the total number of lymphocytes.

Conclusion

Patients successfully treated with NVP‐based HAART have a smaller increase in absolute CD4 cells compared with those treated with PI‐based HAART.

     

Successful use of protease inhibitors in HIV-infected haemophilia patients

The haemophilias are a group of inherited haemostatic disorders that require regular clotting factor replacement therapy in the severe and moderately severe subgroups. Prior to the introduction of adequate viral inactivation methods in 1985, haemophilia patients were at exceptionally high risk of contracting blood-borne viruses from factor concentrates as each batch was derived from the plasma of thousands of donors. As a result, approximately 60% of these patients were infected with HIV between 1979 and 1985, and HIV infection now contributes significantly to the morbidity and mortality seen in this group.
Protease inhibitors (PIs) have been shown to significantly log reduce viral loads and increase CD4 cell counts in HIV-infected individuals. Recently, there has been concern about their use in HIV-infected haemophilia patients following increased bleeding episodes in some patients during PI therapy. We prospectively studied the effect of PI therapy in 20 HIV-infected haemophilia patients at our centre over a 6-month period. The mean increase in CD4 cell count was 70 × 10⁶/l and the mean log decrease in viral load was 1.59 over the study period. Gastrointestinal side-effects (nausea and vomiting in five, diarrhoea in two) were the most frequent and resulted in discontinuation of the medication in two patients. Factor concentrate usage for the group on and off study was similar. One severe FVIII patient reported a single episode of an unusual bleed which responded promptly to FVIII concentrate infusion. The significant clinical and laboratory benefits in terms of HIV disease and the paucity of added bleeding complications suggest that PI therapy should not be withheld from HIV-infected haemophilics. Further prospective studies evaluating the efficacy and possible haemostatic complications related to these promising inhibitors of the HIV protease are needed.     

Switching from suppressive protease inhibitor-based regimens to nevirapine-based regimens: a meta-analysis of randomized controlled trials

Objectives

We performed a meta‐analysis to assess the efficacy and safety of switching from protease inhibitor (PI)‐ to nevirapine (NVP)‐based regimens in HIV‐infected patients in whom virological suppression had been achieved.

Methods

Six trials (550 patients) were analysed. The demographics showed that 11–48% of participants were female and 40–53% had hepatitis C or B virus infection, and the mean CD4 lymphocyte count was >500 cells/μL at study entry.

Results

NVP‐based regimens showed noninferiority compared with continuation of PI therapy to maintain virological suppression in ‘intention to treat’ (80 vs. 78%; P=0.35) and ‘on treatment’ analyses (91 vs. 89%; P=0.10). Overall rates of discontinuation because of adverse events were similar in the two groups (11 vs. 10%; P=0.79). However, NVP‐based therapies caused more discontinuations because of liver toxicity than PI‐based therapies (7 vs. 0%; P=0.0009). At the end of follow‐up there was no statistical difference in CD4, cholesterol, triglyceride and body shape measurements between the two groups. Two studies reported greater improvement in quality of life in patients who were switched to the NVP group.

Conclusions

Switching from suppressive PI‐ to NVP‐based regimens is virologically and immunologically safe; however, the risk of liver toxicity requires monitoring of clinical symptoms and liver chemistry during NVP therapy.     

HIV/AIDS patients’ perspectives on adhering to regimens containing protease inhibitors

OBJECTIVE: To gather qualitative data regarding HIV/AIDS patients’ perspectives about HIV-1 protease inhibitors (PIs), and about their experiences taking and adhering to regimens containing PIs. DESIGN: Six focus groups of persons under care for HIV were conducted between September and November 1996 regarding participants’ knowledge, awareness, experiences when taking, and adherence to antiretroviral regimens containing PIs. An identical discussion guide was used to facilitate all six groups. Focus group proceedings were audiotaped, transcribed, coded for themes, and analyzed qualitatively. SETTING: HIV/AIDS practices of three teaching hospitals and two community health centers. PATIENTS/PARTICIPANTS: Fifty-six patients with HIV disease: 28 men and 28 women. MEASUREMENTS AND MAIN RESULTS: Knowledge and positive impressions of PIs were prevalent among this diverse group of persons with HIV, and did not differ by race/ethnicity or gender. Most knew that these were new, potent medications for treating HIV/AIDS. Networks of persons with HIV and medical providers were the most important information sources. Those taking PIs were aware that adherence to the regimen is important, and most were using special strategies to maximize their own adherence, but expressed considerable frustration about the central role these medication regimens had assumed in their life. A subset who did not believe they would adhere to these regimens had declined treatment with them. Motivating factors for taking and adhering to these complex regimens were improving CD4 counts and viral loads and the patient-provider relationship. CONCLUSIONS: Among those with HIV/AIDS, awareness of PIs and their effectiveness is substantial, owing to the impact of informal networks and medical providers. This early positive “reputation” of PIs may enhance motivation for adherence. Those who are taking PIs invest substantial effort adhering to these complex regimens, but resent the need to make medications the focus of their lives. Preliminary findings of this study were presented at the Society of General Internal Medicine annual meeting on May 3, 1997, and the National Conference on Women and HIV on May 6, 1997. This research was supported by a Generalist Physician Faculty Scholar Award from the Robert Wood Johnson Foundation and a grant from Merck and Co., Inc.     

Dyspepsia in HIV-infected patients under highly active antiretroviral therapy

BACKGROUND AND AIM: Upper gastrointestinal symptoms, mainly dyspepsia, are common adverse effects in patients under highly active antiretroviral therapy (HAART). Whether it is worthwhile to perform endoscopy early in their treatment is a matter of debate. We have done a prospective study of the prevalence and the etiology of endoscopic lesions in a large cohort of dyspeptic adult HIV-infected patients under HAART, according to their immunological status. METHODS: 528 (334 men and 194 women, mean age 38) HIV-infected patients under HAART with epigastric pain and/or nausea and vomiting underwent upper endoscopy. Patients were classified in two groups, according to CD4 cells counting (>200 cells/mm(3) or < or =200 cells/mm(3)). Gastric and duodenal biopsies were taken from normal mucosa and any lesion found. RESULTS: Gastric mucosa alterations were seen in 61.74% of patients (40.71% erythema, 18.38% erosion and 2.65% ulcer). Duodenum mucosa alterations were seen in 25.37% of patients, mainly erosions (19.50%) and ulcer (3.59%). There was no difference in endoscopic findings according to CD4 cell count groups. Chronic active gastritis was shown in 459 patients (86.93%). H. pylori infection was seen in 32.38%, and it was more prevalent in the group with CD4 > 200 (p < 0.01). Opportunistic infections and malignancies were seen exclusively in patients with CD4 < or = 200. CONCLUSIONS: Most of the endoscopic lesions in dyspeptic HIV-infected patients under HAART were not related to AIDS. Upper endoscopy was more helpful in dictating clinical treatment in patients with low CD4 counts (< or =200) and should be done earlier in this group.     

Incidence of and risk factors for bacteraemia in HIV-infected adults in the era of highly active antiretroviral therapy

Background

HIV‐infected patients have an increased risk for bacteraemia compared with HIV‐negative patients. Few data exist on the incidence of and risk factors for bacteraemia across time in the current era of highly active antiretroviral therapy (HAART).

Methods

We assessed the incidence of bacteraemia among patients followed between 2000 and 2008 at 10 HIV Research Network sites. This large multisite, multistate clinical cohort study collected demographic, clinical and therapeutic data longitudinally. International Statistical Classification of Diseases and Related Health Problems (ICD)‐9 codes were examined to identify all cases of in‐patient bacteraemia. Logistic regression analysis was used to assess risk factors for bacteraemia and trends over time in the odds of bacteraemia.

Results

A total of 39 318 patients were followed for 146 289 person‐years (PY). During the study period, there were 2025 episodes of bacteraemia (incidence 13.8 events/1000 PY). The most common bacteraemia diagnosis was ‘bacteraemia, not otherwise specified (NOS)’ (51%) followed by Staphylococcus aureus (16%) and Streptococcus species (6.5%). In multivariate analysis, the likelihood of bacteraemia was found to have increased in 2005–2008, compared with 2000. Other factors associated with higher odds of bacteraemia included a history of injection drug use (IDU), age ≥50 years, Black race and greater immunosuppression.

Conclusions

The likelihood of bacteraemia has risen slightly in recent years. Patients who are Black or have a history of IDU are at higher risk. Further research is needed to identify reasons for this increase and to evaluate programmes designed to reduce the bacteraemia risk.     

A randomized controlled trial investigating the efficacy and safety of switching from a protease inhibitor to nevirapine in patients with undetectable viral load

OBJECTIVE: To assess the antiviral efficacy and safety of switching from a protease inhibitor (PI) to nevirapine in patients with long-term HIV-1 RNA suppression on PI-containing regimens, and to assess its influence in the adherence to treatment. METHODS: In an open-label multicentre study, 160 HIV-infected patients with undetectable viral load for at least 6 months on a PI-containing regimen were randomized to either continue with their PI regimen (n=79) or replace PI with nevirapine (n=81). Clinical assessment included plasma HIV-1 RNA, blood chemistry, haematology, lymphocyte counts and adverse events reports. Adherence to treatment and lipodystrophy syndrome were assessed by patient self-reporting. RESULTS: Treatment efficacy was equivalent in the two arms, for patients with viral loads either above or below 100 000 HIV-1 RNA copies/mL. The increase in CD4 cell count was significant in both arms (P<0.00001) but the average CD4 cell count at 48 weeks was slightly higher in the nevirapine arm (596 vs. 569; P=0.1588). The number of patients with severe hypertriglyceridaemia (>400 mg/dL) after 48 weeks of treatment decreased in the nevirapine arm (from 11 to six), but increased in the PI arm (from four to 11) and led to treatment discontinuation in two patients. Lipodystrophy changes increased in 15% of patients in the PI arm but decreased in 4% of patients in the nevirapine arm. Finally, although adherence was similar in the two arms, patients reported that it required significantly less effort to stay on treatment in the nevirapine arm. Conclusions The results indicate that switching from PI to nevirapine is as effective as continuing with PI for maintaining viral control, even in patients with baseline viral load above 100,000 copies/mL. In addition, reductions in hypertriglyceridaemia and lipodystrophy and in the effort required to stay on treatment were observed.     

Factors associated with renal dysfunction within an urban HIV-infected cohort in the era of highly active antiretroviral therapy

Background

Kidney disease remains a prevalent problem in HIV care. The contribution of highly active antiretroviral therapy (HAART), HIV disease factors and traditional factors needs further evaluation.

Methods

A cross‐sectional study of all patients seen at an HIV outpatient clinic during 2005 was performed. All data were collected from medical record review. Multivariate regression modelling was used to identify independent predictors of lower glomerular filtration rate (eGFR) and chronic renal failure (CRF) from factors significant in univariate analysis. eGFR was calculated using the simplified modification of diet in renal disease equation. Results were compared with those for persons from the National Health and Nutrition Examination Survey (NHANES) matched for age, race and gender.

Results

Of 845 HIV‐infected persons, 64% were men and 34% were Caucasian, and the mean age was 39.8 years. Thirty per cent of the patients had proteinuria and 43% had eGFR<90 mL/min/1.73 m². Persons on HAART (63%) had a lower mean eGFR than those not on HAART (92.0 vs. 101.6). In multivariate analyses, significant predictors of eGFR decline were diagnoses of hypertension, hyperlipidaemia, proteinuria, use of tenofovir or stavudine, and lower viral load. Compared with those in NHANES, HIV‐infected persons had a lower mean eGFR (94.9 vs. 104.2) and a higher prevalence of CRF (8%vs. 2%).

Conclusion

In this cohort, the prevalence of CRF is low, but remains higher than that of the general population. Clinicians should routinely screen for early asymptomatic kidney disease to address risk factors that can be treated.     

不同抗HIV治疗方案对HCV与HIV合并感染者丙型肝炎疾病进展的影响

目的探讨以蛋白酶抑制剂（Hs）或非核苷类反转录酶抑制剂（NNRTIs）为主方案治疗HCV／HIV合并感染者,对患者丙型肝炎疾病进展的影响。方法收集初次就诊的273例HCV／HIV合并感染者为研究对象。分别用PIs（PIs组。135例）或NNRTIs（NNRTIs组,138例）为主的方案治疗1年。实验室检查治疗前、后HCVRNA、AST、ALT、TBil、白蛋白（Alb）、层粘连蛋白（LN）、甘胆酸（CG）、Ⅲ型前胶原（PCⅢ）、Ⅳ型胶原（CⅣ）、凝血酶原活动度（PTA）、胆碱酯酶（ChE）等指标。计量资料经Kolmogorov—Smimov检验。非正态分布数据采用Mann Whitney U检验。结果治疗后NNRTIs组PTA、ChE、TBil、Alb、ALT、AST、CG、LN显著高于PIs组。PTA分别是77％（67％,109％）和68％（56％,91％）;ChE分别是6717．00（5951．00,7622．00）和5862．00（4392．00,8539．25）U／L;TBil分别是10．95（8．10,14．32）和8．60（8．00,9．50）μmoL／L;Alb分别是43．90（39．65,48．20）和38．90（36．00,45．00）mmol／L;ALT分别是52．50（30．00,93．50）和36．20（30．30,40．40）U／L;AST分别是49．00（33．00,80．00）和31．30（29．70,38．70）U／L;CG分别是16．78（3．26,29．32）和3．26（1．02,6．88）μg/ml;LN分别是34．40（16．71,46．54）和34．05（33．42,64．33）ng／ml,两组比较差异有统计学意义（P〈0．05或P〈0．01）。结论NNRTIs为主治疗HCV／HIV合并感染的患者可以加重其丙型肝炎进展。     

Polymorphisms in HIV-1 subtype C proteases and the potential impact on protease inhibitors

Objectives (i) To review data on the genetic profile of the protease (PR) gene of human immunodeficiency virus (HIV)‐1‐C primary isolates relative to HIV‐1‐B; (ii) to examine data on the susceptibility of HIV‐1‐C isolates harbouring polymorphisms to PR inhibitors (PI) and the development of resistance; and (iii) to identify gaps required for an improved understanding of the role of polymorphisms in resistance development of HIV‐1‐C to PI. Method Literature review. Results Significant differences exist between the baseline nucleotide and amino acid sequences of PR of HIV‐1‐B and HIV‐1‐C. Some of the amino acid substitutions seen in HIV‐1‐B when exposed to PI occur naturally in HIV‐1‐C isolates. Studies used different methodologies and interpretation systems to evaluate the phenotypic significance of polymorphisms seen in subtype C viruses, with conflicting outcomes. The evolutionary path to the resistance of HIV‐1‐C to PI may be different from that of HIV‐1‐B. Conclusions Infection with HIV‐1‐C is driving the AIDS epidemic in regions of the world with the most urgent needs for the management of the disease. More and more individuals will require PR inhibitors in second‐line therapies, as access to antiretrovirals progresses. It is proposed that a standardized protocol be adopted to evaluate the phenotypic significance of the highly polymorphic HIV‐1‐C PR to PR inhibitors with the aim of better informing the tailoring of treatment regimens for optimal clinical benefit.     

Incidence and risk factors of bacterial pneumonia requiring hospitalization in HIV-infected patients started on a protease inhibitor-containing regimen

OBJECTIVE: To describe the incidence and risk factors of bacterial pneumonia occurring in patients treated with antiretrovirals. METHODS: In the ongoing APROCO (Anti-proteases) cohort, 1281 patients at the initiation of a protease inhibitor (PI)-containing antiretroviral regimen were enrolled from 1997-1999. All events requiring hospitalization during follow up are recorded. Of these, bacterial pneumonia was defined as the occurrence of a new pulmonary infiltrate with fever and either evidence of a bacteriological cause (definite cases) or favourable outcome with antimicrobial therapy (presumptive cases). Risk factors of bacterial pneumonia were studied using survival analyses. RESULTS: During a median follow up of 43 months, 29 patients had at least one episode of bacterial pneumonia, giving an incidence of 0.8/100 patient years. The 11 definite cases were attributable to Streptococcus pneumoniae (n=9), Legionella pneumophila (n=1) and Haemophilus influenzae (n=1). In multivariate analysis, bacterial pneumonia was significantly more frequent in older patients, injecting drug users, patients having a CD4 cell count>500 cells/microL at baseline and patients who initiated PI therapy with nonboosted saquinavir. It was significantly less frequent in nonsmokers. The occurrence of bacterial pneumonia was also associated with lower self-reported adherence to antiretroviral therapy and to higher plasma HIV-1 RNA levels during follow-up. CONCLUSIONS: Bacterial pneumonia occurs rarely in patients treated with a PI-containing regimen and may be associated with virological failure.     

Characterization of viro-immunological responses in a closely followed cohort of heavily pretreated patients: evidence from the GenPheRex Study

Objectives

To assess prevalence and predictive factors of viro‐immunological discordant trends in a cohort of heavily pretreated patients.

Methods

Factors associated with viro‐immunological discordant trends either as categorical or continuous measures have been studied in 159 heavily pretreated HIV‐positive patients from a multicentre prospective study of real‐ vs. virtual‐phenotype. Univariate and multivariate logistic regressions were used to assess risk factors for categorical discordant responses, ceasing follow‐up at week 32 since enough patients had been on the original drug combination for a sufficient amount of time to evaluate their immune response. Complementary linear regression analysis was performed over the entire 48 weeks' follow‐up considering CD4 and plasma viral load (pVL) as continuous measures.

Results

Among 58 virological responder patients (≥1 log₁₀ HIV‐1 RNA copies/mL decrease) and 101 virologically non‐responders, immunological discordances (increase in CD4 count ofP<0.001), also the use of protease inhibitors (PIs) in the salvage regimen (HR 36.57, 95%CI 15.45–57.68; P<0.001) and >8 months on treatment (HR 41.64, 95%CI 19.27–64.01; P<0.001) correlated with highly significant immune recovery.

Conclusions

These data confirm that therapy, possibly including PIs, should be continued in heavily pretreated patients and that hard‐to‐reach pVL undetectability is not essential to obtain immunologic recovery; however, this is strongly increased by the degree of pVL reduction that should be achieved.