Findings from the first national clinical audit of treatment for people with HIV

Objectives

We reviewed the impact of and assessed adherence to British HIV Association (BHIVA) guidelines in routine clinical practice. Feedback has been provided to clinical centres to facilitate any necessary change.

Methods

We used a questionnaire to gauge clinicians' views on the guidelines and availability of antiretroviral therapy (ART) drugs and specialized tests. A case note review of 2044 patients was conducted to assess adherence to guideline recommendations plus patterns of use of HIV resistance testing.

Results

Most clinicians (74.1%) report that BHIVA guidelines have influenced care at their centres. A significant minority report problems with access to specialized tests. Most patients who started ART did so at CD4 counts lower than guidelines recommend but in most cases this reflected the CD4 count at diagnosis of HIV. Of patients on ART, an overwhelming majority (97.6%) were receiving three or more drugs. Of those on three or more drugs, 58.9% had latest viral load (VL) below 50 HIV‐1 RNA copies/mL and a further 18.1% below 500 copies/mL. Only 19.3% of patients had been tested for HIV resistance, of whom more than half showed resistance to more than one class of drugs.

Conclusions

This clinical audit provides encouraging evidence of the quality of care offered to people with diagnosed HIV in the UK. However late diagnosis means most people start ART at a more advanced stage than guidelines recommend.

     

Naively changing HAART

Background

Few UK studies have systematically investigated which antiretroviral therapy (ART) combinations HIV‐infected people are commenced on, when they start and reasons for stopping or changing their regimens.

Objective

To describe when HIV‐infected ART‐naive patients started first‐, second‐ or third‐line triple ART, classes of drugs prescribed and whether stopping ART was associated with virological, immunological or clinical indicators of treatment failure.

Design

A multicentre prospective open cohort study, employing the National Prospective Monitoring System on the use, cost and outcome of HIV service provision in UK hospitals‐HIV Health‐economics Collaboration (NPMS‐HHC).

Setting

Five hundred and eighty‐five ART‐naive patients seen in one London and two non‐London HIV clinics between 1 January 1998 and 31 December 1999.

Results

Of 4044 HIV‐infected individuals seen, 585 (15%) were ART naive. Median time interval (interquartile range, IQR) between HIV diagnosis and starting triple ART was 800 (63–2094) days. Median CD4 count when first diagnosed with HIV infection was 278 (IQR 127–481) cells/µL which dropped to 190 (IQR 86–297) cells/µL when starting triple ART. Of these 585 patients, 162 started second‐line and 46 third‐line ART during the study period. Of those patients who stopped ART, 51% did not have evidence of virological, immunological or clinical indicators of therapy failure.

Conclusions

Reasons for the delay between diagnosis of HIV infection and starting ART are varied. The large proportion of individuals who stopped ART for reasons other than virological, immunological or clinical indicators of therapy failure, are most likely due to drug‐associated toxicity. Both of these findings need to be elucidated in greater detail through prospective studies.

     

Later onset of herpes zoster-associated immune reconstitution inflammatory syndrome

Objectives

The aim of the study was to determine whether immune reconstitution inflammatory syndrome (IRIS) associated with herpes zoster occurs on a different time frame from other instances of IRIS.

Methods

Statistical analysis of onset times of herpes zoster‐associated IRIS and other cases of IRIS was carried out in a retrospective cohort starting antiretroviral therapy at advanced stages of HIV infection.

Results

Herpes zoster‐associated IRIS was significantly more frequent after the first 3 months of successful highly active antiretroviral therapy (HAART), than other instances of IRIS (IRIS associated with tuberculosis, Mycobacterium avium complex, Kaposi's sarcoma, etc.) which mainly occurred during the first 3 months of treatment.

Conclusions

The characteristic onset time pattern of herpes zoster‐associated IRIS, coincident with the second phase of immune recovery under HAART, suggests that the immune recovery events underlying herpes zoster‐associated IRIS are different from those underlying other types of IRIS. Our findings may be useful in improving the follow‐up of individuals who start HAART at an advanced stage of HIV infection.

     

Antiretroviral therapy-induced psychosis: case report and brief review of the literature

Objective

We present a case of psychosis in an individual with known HIV infection whose symptoms developed approximately 1 month following the commencement of combination antiretroviral therapy consisting of abacavir (ABC), nevirapine and combivir. She presented with severe persecutory delusions, accompanied by mutism, posturing and catatonia. Following cessation of therapy and the introduction of a low‐dose antipsychotic, her mental state resolved to a stable premorbid level, and no further disturbances of behaviour were noted. Furthermore, when re‐challenged with the above combination minus ABC, there were no further episodes of psychosis. It is proposed that the aetiology of the psychosis was related to her antiretroviral therapy.

Methods

Cessation of antiretroviral medication and initiation of antipsychotic medication with appropriate monitoring and assessment.

Results

Subjective and objective improvements in psychotic symptoms and presentation.

Conclusion

The current case suggests that sudden onset psychotic disturbances in HIV‐infected individuals in the absence of other known organic or other causal factors could be related to treatment with antiretroviral therapy, and that cessation of this can markedly improve psychiatric morbidity. Furthermore, treatment with antipsychotic medication can lead to alleviation of psychotic symptoms and enable the re‐introduction of antiretroviral medication.

     

National review of first treatment change after starting highly active antiretroviral therapy in antiretroviral-naïve patients

Objectives

The aim of the study was to explore the factors surrounding modification of the first antiretroviral (ARV) regimen where drug switch occurred 3 months or more after initiation. Reference was made to the British HIV Association (BHIVA) guidelines on HIV management.

Methods

A case note and questionnaire‐based audit was carried out.

Results

Toxicity was the single most important reason for ARV change and was the only, or a contributory, cause in over half the patients. Virological failure, adherence issues, requirement for treatment simplification, and patient request were other significant reasons cited. In one‐third of those with virological failure, six or more months had elapsed between first detection and the time of switching to a new ARV regimen.

Conclusions

This audit demonstrated broad adherence to the BHIVA guidelines, although the long time before switching ARVs in the setting of virological failure was of some concern, particularly given the continuing and significant occurrence of primary ARV resistance in the UK.

     

CD4 percentage is an independent predictor of survival in patients starting antiretroviral therapy with absolute CD4 cell counts between 200 and 350 cells/microL

Objective

To determine the prognostic value of baseline CD4 percentage in terms of patient survival in comparison to absolute CD4 cell counts for HIV‐positive patients initiating highly active antiretroviral therapy (HAART).

Methods

A population‐based cohort study of 1623 antiretroviral therapy‐naïve HIV‐positive individuals who initiated HAART between 1 August 1996 and 30 June 2002 was conducted. Cumulative mortality rates were estimated using Kaplan–Meier methods. Cox proportional hazards regression was used to model the effect of baseline CD4 strata and CD4 percentage strata and other prognostic variables on survival. A subgroup analysis was conducted on 417 AIDS‐free subjects with baseline CD4 counts between 200 and 350 cells/μL.

Results

In multivariate models, low CD4 percentages were associated with increased risk of death [CD4%<5, relative hazard (RH)=4.46; CD4% 5–14, RH=2.43; P<0.01 for both] when compared with those subjects with an initial CD4 fraction of 15% or greater, but had less predictive value than absolute CD4 counts. In subgroup analyses where absolute CD4 strata were not associated with mortality, a baseline CD4 fraction below 15% [RH=2.71; 95% confidence interval (CI) 1.20–6.10], poor adherence to therapy and baseline viral load >100 000 HIV‐1 RNA copies/mL were associated with an increased risk of death.

Conclusion

CD4 percentages below 15% are independent predictors of mortality in AIDS‐free patients starting HAART, including those with CD4 counts between 200 and 350 cells/μL. CD4 percentage should be considered for inclusion in guidelines used to determine when to start therapy.

     

An audit of antiretroviral treatment use in HIV-infected patients in a London clinic: the limitations of observational databases when auditing antiretroviral treatment use

Objective

To audit the use of antiretroviral (ARV) treatment in a large treatment clinic in the UK against the British HIV Association (BHIVA) ARV treatment guidelines.

Methods

All patients under follow‐up between 1st January 2000 and 1st January 2001 were included. The most recent CD4 count and HIV RNA level prior to 1st January 2001, and the nadir CD4 count and peak HIV RNA level over follow‐up, were used to identify which patients should be receiving HAART according to the guidelines.

Results

One thousand two hundred and sixty‐four patients were included in the analysis (63.8% homosexual, 29.0% heterosexual risk; 72.9% white; 79.2% male). Almost half of patients had ever had a CD4 count below 200 cells/µL and over 80% had previously had a viral load above 4 log₁₀ HIV‐1 RNA copies/mL. Under 2000 BHIVA guidelines, treatment would be recommended in 77.4% patients. Overall, 819 patients were receiving ARV therapy. Two hundred and eighty‐five patients were not receiving treatment when guidelines suggest they should (including 33 patients who were receiving regimens not recommended in the guidelines). These patients were younger, less likely to be homosexual and had higher CD4 nadirs than those who were receiving ARV treatment. Almost half of these patients had previously received ARV therapy but were not currently receiving it.

Conclusion

Only a small proportion of patients at our centre were not receiving ARV treatment in line with national guidelines. While genuine reasons may exist for these departures from optimal care, this may simply reflect the limitations of using observational databases when auditing treatment use in a clinic setting.

     

Superior virological response to boosted protease inhibitor-based highly active antiretroviral therapy in an observational treatment programme

Background

The use of boosted protease inhibitor (PI)‐based antiretroviral therapy has become increasingly recommended in international HIV treatment consensus guidelines based on the results of randomized clinical trials. However, the impact of this new treatment strategy has not yet been evaluated in community‐treated cohorts.

Methods

We evaluated baseline characteristics and plasma HIV RNA responses to unboosted and boosted PI‐based highly active antiretroviral therapy (HAART) among antiretroviral‐naïve HIV‐infected patients in British Columbia, Canada who initiated HAART between August 1997 and September 2003 and who were followed until September 2004. We evaluated time to HIV‐1 RNA suppression (<500 HIV‐1 RNA copies/mL) and HIV‐1 RNA rebound (≥500 copies/mL), while stratifying patients into those that received boosted and unboosted PI‐based HAART as the initial regimen, using Kaplan–Meier methods and Cox proportional hazards regression.

Results

During the study period, 682 patients initiated therapy with unboosted PI and 320 individuals initiated HAART with a boosted PI. Those who initiated therapy with a boosted PI were more likely to have a CD4 cell count <200 cells/μL and to have a plasma HIV RNA>100 000 copies/mL, and to have AIDS at baseline (all P<0.001). However, when we examined virological response rates, those who initiated HAART with a boosted PI achieved more rapid virological suppression [relative hazard 1.26, 95% confidence interval (CI) 1.06–1.51, P=0.010].

Conclusions

Patients prescribed boosted PIs achieved superior virological response rates despite baseline factors that have been associated with inferior virological responses to HAART. Despite the inherent limitations of observational studies which require this study be interpreted with caution, these findings support the use of boosted PIs for initial HAART therapy.

     

Estimating the effect of antiretroviral treatment during HIV seroconversion: impact of confounding in observational data

Objective

To assess whether treatment with antiretroviral drugs within the first 3 months of infection with HIV affects medium‐term health outcomes.

Design and methods

Data from 20 cohorts in Europe and Australia were used Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE). Analysis was restricted to persons seroconverting in 1988–1998 who started antiretroviral treatment in the first 3 months or 1–2 years from seroconversion. The relationship between times to low CD4 count, AIDS and death and time of initiation of treatment was estimated using proportional hazards models.

Results

Seroconversion illness was more common in those who began antiretroviral treatment in the first 3 months (73%) than in those who started treatment within 1–2 years post‐seroconversion (33%). Subjects receiving early antiretroviral treatment had times to AIDS and to CD4 counts <200 cells/μL that were intermediate between those of subjects starting treatment within 1–2 years and those of the subset of these subjects starting treatment within 1–2 years who also had a prior CD4 count of >350 cells/μL and no prior AIDS diagnosis.

Conclusions

On the basis of these analyses, the effect of antiretroviral treatment initiation during HIV seroconversion is uncertain. It may result in lower rates of progression compared with starting antiretroviral treatment at 1–2 years, but the early antiretroviral treatment group had a similar or even higher incidence of low CD4 counts and AIDS events than the group who started antiretroviral treatment within 1–2 years with CD4 counts over 350 cells/μL and no prior AIDS diagnosis. Estimates of the effect of early treatment are probably confounded with a number of factors, including, in particular, reasons for treatment initiation.

     

Uptake of and virological response to antiretroviral therapy among HIV-infected former and current injecting drug users and persons in an opiate substitution treatment programme: the Swiss HIV Cohort Study

Objectives

The aim of the study was to investigate the influence of continued injecting drug use, enrolment in an opiate substitution treatment programme (OSTP), or cessation of injecting drug use on the uptake and course of antiretroviral therapy (ART).

Design

A prospective observational study of all participants in the Swiss HIV Cohort Study followed between 1997 and 2006 was carried out.

Methods

We distinguished four groups of former or current injecting drug users (IDUs): (i) abstinent former IDUs; (ii) persons in OSTPs without concomitant injecting drug use; (iii) persons in OSTPs with concomitant injecting drug use; (vi) current IDUs. These groups were compared with a group of patients who had never been IDUs. Factors related to ART uptake and virological endpoints were analysed using logistic generalized estimating equations.

Results

We followed 8660 participants for 48 477 person‐years; 29.7% were in the IDU HIV transmission group. The likelihood of being on ART at biannual visits was lower among individuals in OSTPs with concomitant injecting drug use [odds ratio (OR) 0.79; 95% confidence interval (CI) 0.71–0.89] and current IDUs (OR 0.80; 95% CI 0.67–0.96), compared with those who had never been IDUs (reference), abstinent former IDUs (OR 1.13; 95% CI 1.02–1.25) and individuals in OSTPs without injecting drug use (OR 1.18; 95% CI 1.06–1.31). The likelihood of suppressed viral replication on ART was similar among those who had never been IDUs, abstinent former IDUs and individuals in an OSTP without injecting drug use, and lower among those in OSTPs with concomitant drug use (OR 0.82; 95% CI 0.72–0.93) and current IDUs (OR 0.81; 0.65–1.00). Adherence to ART was decreased among persons with continued injecting drug use, and correlated with virological outcome.

Conclusions

Uptake of and virological response to ART were improved among abstinent former IDUs and persons in OSTPs without concomitant injecting drug use, compared with persons with continued injecting drug use.

     

Persistence of CCR5 usage among primary human immunodeficiency virus isolates of individuals receiving intermittent interleukin‐2

Objective

To investigate the impact of intermittent interleukin‐2 (IL‐2) plus combination antiretroviral therapy (cART) on HIV‐1 entry co‐receptor use.

Methods

Primary HIV‐1 isolates were obtained from 54 HIV‐1‐positive individuals at baseline and after 12 months using co‐cultivation of peripheral blood mononuclear cells (PBMC) with activated PBMC of HIV‐negative healthy donors. HIV‐1 co‐receptor use was determined on U87‐CD4 cells.

Results

Fourteen out of the 21 (67%) IL‐2‐treated individuals harbouring a primary CCR5‐dependent (R5) HIV‐1 isolate at baseline confirmed an R5 virus isolation after 12 months in contrast to 3 out of 7 (43%) of those receiving cART only. After 12 months, only 1 R5X4 HIV‐1 isolate was obtained from 21 cART+IL‐2‐treated individuals infected with an R5 virus at entry (5%) vs. 2/7 (29%) patients receiving cART alone, as confirmed by a 5‐year follow‐up on some individuals.

Conclusions

Intermittent IL‐2 administration plus cART may prevent evolution towards CXCR4 usage in individuals infected with R5 HIV‐1.

     

The value of serum albumin in pretreatment assessment and monitoring of therapy in HIV/AIDS patients

Objectives

We sought to examine the utility of serum albumin measurement in staging AIDS and monitoring patients' response to therapy.

Methods

The possible importance of serum albumin measurement in assessing AIDS stage and in monitoring the response to highly active antiretroviral therapy using CD4 cell count and body weight as parameters was examined in 185 consecutive HIV‐infected, therapy‐naïve individuals who were recruited for antiretroviral therapy at the university of Ilorin Teaching Hospital. The regimen included lamivudine, stavudine and nevirapine. The diagnosis of AIDS was established through a combination of clinical features and HIV seropositivity using two different enzyme‐linked immunosorbent assay techniques. Serum albumin level was determined by the Bromocresol green method, while the CD4 lymphocyte count was obtained using the Dynal T4 count method. Body weight was measured in kilograms with light clothes on.

Results

There were significant positive correlations between pretreatment albumin and both pretreatment CD4 cell count and pretreatment weight, and between post‐treatment albumin and both post‐treatment weight and post‐treatment CD4 cell count up to a count of 700 cells/μL. There were also significant positive correlations between increase in serum albumin and both increase in body weight and duration of treatment.

Conclusions

We conclude that, in developing countries where many patients may not be able to afford to pay for CD4 cell counts and viral load tests, which are the traditional markers for HIV disease, serum albumin would be a very useful surrogate test for predicting severity of HIV infection and for clinical monitoring of response to antiretroviral therapy.

     

Promoting high standards of care for women living with HIV: position statement from the Women Against Viruses in Europe Working Group

Objectives

Gender‐related factors can influence management decisions, treatment outcomes and the overall long‐term wellbeing of people living with HIV (PLWH). The Women Against Viruses in Europe (WAVE) Working Group was established to promote the health and wellbeing of women living with HIV (WLWH). WAVE is part of the European AIDS Clinical Society (EACS) and organizes annual workshops to discuss different issues in the management of WLWH.

Methods

In 2016, 34 WAVE members including community representatives, HIV clinicians and researchers met to discuss standards of care for WLWH and to review current guidelines. Participants focused on three different themes: (1) access to and engagement and retention in care; (2) monitoring of women on antiretroviral therapy and management of comorbidities; and (3) review of EACS treatment guidelines.

Results

Five priority areas for optimizing the care of WLWH were identified: (1) psychosocial aspects of HIV diagnosis and care; (2) mental health and wellbeing; (3) pharmacokinetics, toxicity and tolerability of antiretroviral therapy; (4) coinfections and comorbidities; and (5) sexual and reproductive health. WAVE recommendations are provided for each of these areas, and gaps in knowledge and needs for changes in currently existing standards are discussed.

Conclusions

This position statement provides an overview of the key recommendations to optimize the care of WLWH that emerged during the 2016 WAVE workshop.

     

Fat distribution is altered in HIV-infected men without clinical evidence of the HIV lipodystrophy syndrome

Objective

To determine if fat distribution is altered in HIV‐infected men without clinical evidence of lipodystrophy.

Methods

In a cross‐sectional design, 14 protease inhibitor (PI)‐treated men with lipodystrophy and 12 PI‐treated and five PI‐naive men without clinical evidence of lipodystrophy underwent body composition and fat distribution analysis by dual‐energy X‐ray absorptiometry and computed tomography. Their fat distribution was compared to 43 uninfected male controls matched for age and BMI.

Results

The percent of body fat in the trunk of men with HIV lipodystrophy was significantly greater compared to both HIV‐infected and healthy controls. The percentage of body fat in the extremities was significantly lower in men with HIV lipodystrophy compared to both HIV‐infected and healthy controls. HIV‐infected men without clinical evidence of lipodystrophy also had a significantly greater percentage of total body fat in the trunk and a significantly lower percent of body fat in the extremities compared to healthy controls. Among the HIV‐infected men, age was an independent predictor of truncal and extremity adiposity.

Conclusion

This study suggests that a continuum of change is present in the adipose organ of HIV‐infected men on antiretroviral therapy. Physical examination alone can miss significant changes in body fat distribution in HIV‐infected patients.

     

Impact of adherence on duration of virological suppression among patients receiving combination antiretroviral therapy

Objective

To assess the effect of adherence to antiretroviral therapy on the duration of virological suppression after controlling for whether or not the patient ever attained a plasma viral load below the limit of detection of sensitive HIV‐1 RNA assays.

Methods

Data were combined from three randomized, blinded clinical trials (INCAS, AVANTI‐2, and AVANTI‐3) that compared the antiviral effects of two‐ and three‐drug antiretroviral regimens. Virological suppression was defined as maintaining a plasma viral load below 1000 copies/mL. Adherence was defined prospectively and measured by patient self‐report.

Results

Adherence did not have a major impact on the probability of achieving virological suppression for patients receiving dual therapy. However, for patients receiving triple therapy, adherence increased the probability of virological suppression, whether the plasma viral load nadir was above or below the lower limit of quantification. Compared to adherent patients with a plasma viral load nadir below the lower limit of quantification, the relative risk of virological failure was 3.0 for non‐adherent patients with a nadir below the limit, 18.1 for adherent patients with a nadir above the limit, and 32.1 for non‐adherent patients with a nadir above the limit.

Conclusion

For patients receiving current three‐drug antiretroviral regimens, adherence to therapy and plasma viral load nadir are important factors determining the duration of virological suppression.