Systematic review of the efficacy and safety of biological therapy for inflammatory conditions in HIV-infected individuals

Abstract

Biologic therapies are injectable immunomodulatory agents directed against specific immune cell or chemical targets. They have transformed the lives of HIV-uninfected individuals with severe inflammatory conditions including psoriasis, rheumatoid arthritis, and ulcerative colitis. The perceived increased infection risk associated with these agents means that HIV-infected individuals have not been included in randomised control trials of these drugs. The literature for use of biologic therapies in HIV-infected populations is limited to case reports and case series. There are additional data on use of rituximab, a monoclonal antibody against B lymphocytes, in the setting of HIV-associated haematological malignancy. We performed a systematic review of efficacy and safety of biologic therapy for inflammatory conditions in HIV-infected individuals. Our systematic review identified 37 treatment episodes with six different biologic agents encompassing 10 different inflammatory conditions. Broadly, efficacy of the agents studied was comparable to reports from HIV-uninfected patients. Both infectious and non-infectious sequelae were also comparable with trial data from HIV-uninfected patients. HIV control, even for the minority of individuals not receiving anti-retroviral therapy (ART) at the time of biologic therapy, was not adversely affected. However, detail was limited concerning ART regimens and both immunological and virological parameters of follow-up. Overall available literature is of very low quality and likely subject to publication bias of successful cases. Firm conclusions are not possible regarding the efficacy and safety of biologic agents in HIV-infected individuals; however, there appear to be sufficient data to warrant inclusion of individuals with well-controlled HIV in future trial studies.

Keywords

HIV biologic therapy dermatology gastroenterology rheumatology

Introduction

Biologic therapies are a class of protein drugs that target specific chemicals or cells in the human immune system. Most licensed biologic agents antagonise cytokines to treat a range of immune-mediated inflammatory diseases (Table 1). More than 90% of biologic therapies used for inflammatory conditions target tumour necrosis factor-alpha (TNF-a).¹ Like other biologic therapy targets, TNF-a has protean pro-inflammatory effects in vivo, such as inflammatory cell recruitment and release of additional cytokines interleukin-1 (IL-1) and IL-6.² Multiple therapeutic mechanisms have been employed to down-regulate its effects, including monoclonal antibodies that target TNF-a directly (e.g. infliximab), and neutralising soluble receptor antagonists (e.g. etanercept). These therapies have transformed care for HIV-negative populations with severe inflammatory conditions. Approximately 70% of anti-TNF-a agents used globally are prescribed for rheumatoid arthritis.³ In the UK, approximately 6% of patients with rheumatoid arthritis (RA), over 12,000 individuals, receive biologic drugs. This is closer to 12% in The Netherlands and Spain where clinical thresholds for biologic therapy are lower.³

Table 1.

Biologic therapies for inflammatory conditions with NICE recommendations up to July 2015.

Biologic agent	Mechanism	Indication	Typical dosing and administration
TNFα inhibitors
Adalimumab	Human Mab to TNFα receptor	AS, CD, JIA, nr-axSpA, Ps, PsA, RA, UC	40 mg weekly – every 2 weeks S/C
Certolizumab	Human Mab to TNFα -specific Fab fragment	AS, nr-axSpA, PsA RA	I: 400 mg 0, 2, 4 weeks; M: 200–400 mg every 2–4 weeks S/C
Etanercept	IgG1-TNFa receptor fusion protein to TNFα	AS, JIA Ps, PsA, RA	25 mg twice weekly or 50 mg once weekly S/C
Golimumab	Human Mab to TNFα receptor		50–100 mg monthly S/C
Infliximab	Chimeric human-murine Mab to TNFα	AS, CD, JIA, Ps, PsA, RA, UC	I: 3 mg/kg 0, 2, 6 weeks; M: 3–7.5 mg/kg every 8 weeks IV
Co-stimulatory signal inhibitors
Abatacept	IgG1-CTLA-4 fusion protein to CD80 and CD86	AS, RA	I: 500–1000 mg 0, 2, 4 weeks; M: every 4 weeks IV; 125 mg once weekly S/C
IL inhibitors
Anakinra	Recombinant IL-1 receptor antagonist	RA	100 mg OD S/C
Secukinumab	Human Mab to IL-17 A	Ps	I: 150–300 mg 0, 1, 2, 3, 4 weeks; M: monthly S/C
Tocilizumab	Human Mab to IL-6	AS, JIA, RA	4–8 mg/kg monthly IV; 162 mg weekly – every 2 weeks S/C
Ustekinumab	Human Mab to IL-12 and IL-23	Ps, PsA	I: 45–90 mg 0, 4 weeks; M: every 12 weeks S/C
B cell inhibitors
Rituximab	Human Mab to CD20	ANCA-associated vasculitis, RA	I: 1 g 0, 2 weeks; M: every 16–24 weeks IV; or 1 g once weekly for 4 doses IV

Mab: monoclonal antibody; IL: interleukin; AS: ankylosing spondylitis; CD: Crohn disease; JIA: juvenile idiopathic arthritis; nr_axSpA: non-radiographic axial spondyloarthritis; Ps: psoriasis; PsA: psoriatic arthritis; RA: rheumatoid arthritis; UC: ulcerative colitis; ANCA: anti-neutrophil cytoplasmic antibody; SC: subcutaneous; IV: intravenous; I: initiation therapy; M: maintenance therapy.

While such agents dampen inflammation, they may also impair appropriate immune responses to infection, although the precise mechanisms are poorly understood.^4,5 In light of this potential increased infection risk, HIV-infected individuals have not been included in randomised controlled trials of biologic therapies alongside elderly and other co-morbid patients that are thought to constitute nearly one-third of current real-life biologic therapy use.⁶ Clinical data reporting use of biologic therapy for inflammatory disease in HIV-infected individuals are largely limited to case reports and case series. Literature reviews are limited to single specialty journals and do not cover the full spectrum of inflammatory conditions that affect HIV-infected individuals. There is a more substantial literature on use of biologic agents as chemotherapy for haematological malignancy in HIV-infected individuals.⁷

In this article, we review published data on the use of biologic therapies used to treat inflammatory conditions in HIV-infected individuals, focusing on, but not limiting discussion to, dermatological, gastroenterological and rheumatological indications. The paper also considers the clinical need for biologic therapy in the treatment of immune-mediated pathology in HIV-infected individuals. We address what might be extrapolated regarding efficacy and safety data from the biologic therapies literature of HIV-associated malignancy and HIV-uninfected populations.

Methods

The primary purpose of this systematic review was to provide an overview of all available studies of biologic treatments of non-malignant and non-lymphoproliferative inflammatory conditions in HIV-positive patients. The review focuses on dermatological, gastrointestinal, and rheumatological indications for biologic therapy. The range of biologic treatments examined was limited to those medications recommended by the National Institute for Health and Care Excellence (NICE) up to 1 July 2015, to pragmatically capture those therapies in current use. Since that date anakinra has been removed from RA treatment guidelines, however, the agent was included in our literature search. The study conducted was in accordance with the PRISMA statement for systematic reviews.

Search strategy

Studies were extracted from search of online databases Embase and Medline (OvidSP) up to 1 July 2015. The search was restricted to adult articles from English literature (Figure 1; Supplementary Material: Additional file 1: Search Strategy).

Figure 1.

Results of literature search.

Initial screening of the titles and abstracts excluded animal studies, basic science studies, duplicate publications, and identified studies primarily on biologic therapy for inflammatory disease in HIV-infected individuals. The full texts of the remaining 52 articles were assessed by two authors for eligibility. Thirty-seven papers were collected for final review. All English language case reports, case series and both prospective and retrospective observational studies were included. References, guidelines and expert opinion were consulted for additional information.

Results

Clinical need is poorly defined in HIV-infected individuals. Prevalence data on inflammatory conditions in HIV-infected populations are based largely on case reports, case series and single-centre studies. These heterogeneous data are further limited by the variable application of standardised disease classifications.⁸ This may be due to the absence of specific diagnostic tests or the lack of collaboration with specialty physicians.⁹ The natural history of inflammatory diseases in HIV-infected individuals is also complex. Onset of inflammatory pathology may be HIV-associated or independent of HIV infection, either preceding or postdating HIV acquisition. Case reports describe occult inflammatory disease unmasked both by HIV-mediated immunosuppression¹⁰ and paradoxically after restitution of the immune system by initiation of antiretroviral therapy (ART).^11,12 Inflammatory manifestations associated with, or intrinsic to, HIV infection are well recognised and may mimic recognised conditions, in particular rheumatologic manifestations.¹³ Describing the confounding effect of HIV infection and ART on any of these processes is complicated and there are no comprehensive long-term prospective data.⁹ Despite this paucity of information, inflammatory conditions are considered common in HIV-infected individuals with possibly different disease courses compared with HIV-uninfected populations.

Specific inflammatory conditions in HIV-infected individuals

Rheumatologic symptoms are common in HIV-infected individuals. In a large retrospective analysis of North American inpatients, arthritis or arthralgia was reported in 5.5% of HIV-infected individuals.¹³ High positive rates of non-specific autoantibodies, such as antinuclear antibodies (ANA) and rheumatoid factor (RF), were described in HIV-infected individuals in studies prior to ART¹⁴; however, seroprevalence after initiating modern ART regimens are thought to be comparable to rates in the general population.¹⁵ Pre-ART era data suggest that rheumatoid arthritis and HIV-infection were mutually exclusive: the decline in CD4+ T cells mitigating lymphocyte-mediated autoimmunity.¹⁶ This dogma may have significantly prejudiced the nomenclature of subsequent studies. Since the introduction of ART, multiple case reports and case series describe new presentations of symmetrical polyarthritis clinically suggestive of Rheumatoid Arthritis. This may affect between 0.1% and 5% of HIV-infected populations, vary geographically, and presentation usually occurs after HIV suppression.⁹ Reveille et al. have proposed that HIV arthritis represents a distinct self-limiting acute arthropathy affecting principally large joints.¹⁷ Ankylosing spondylitis, psoriatic arthritis and reactive arthritis occur in HIV-infected populations although accurate prevalence and natural history studies are not available, with undifferentiated spondyloarthropathy commonly used as a unifying term.⁹

HIV-associated psoriasis most commonly appears as abrupt widespread skin disease or as a severe exacerbation in patients with known psoriasis.¹⁸ Paradoxically, for pathology caused by T cell activation, psoriasis presentation is associated with increasing immunodeficiency.¹⁸ These mechanisms are poorly understood but may relate to the proportional increase in CD8+ T cells late in HIV infection that are thought to mediate skin disease.¹⁹ In advanced HIV infection, generalised skin failure is relatively more common as are co-existence of several psoriasis phenotypes.²⁰ Unlike other inflammatory conditions in the setting of HIV infection, ART is included in formal guidance for treatment of HIV-associated psoriasis.²¹

Of the inflammatory conditions considered in this review, there is least known about the relationship between HIV infection and inflammatory bowel disease. A recent review of the subject identified only 47 eligible patients for study across all relevant literature.²² A small retrospective case-control study suggested that HIV infection predicted lower relapse rates of all causes of inflammatory bowel disease over 18 years of follow-up.²³ The authors speculated that impaired cell-mediated immunity may be responsible.

Non-biologic treatment of inflammatory conditions in HIV-infected individuals

We identified no randomised placebo-controlled trials evaluating safety and efficacy of any treatments for inflammatory conditions in HIV-infected individuals. The small randomised controlled studies of disease-modifying anti-rheumatic drug use in HIV-infected patients were conducted to evaluate their role as HIV therapies, and they did not include patients with autoimmune diseases and the study durations were short.^24–26 However, in patients with well-controlled HIV infection, use of standard immunosuppression, including methotrexate for treatment of inflammatory disease, is supported with caution.^9,21,27 Corticosteroids are widely used in HIV-infected individuals to treat inflammatory conditions. The metabolic and endocrine toxicity of these drugs should be monitored closely in all patients with HIV infection,²⁸ in particular those patients receiving ritonavir-containing ART regimens, which may potently increase the action and duration of corticosteroids. Cushing’s syndrome has been reported following single injections of triamcinolone and methylprednisolone and these should not be co-administered.²⁹

Systematic review of biologic therapies for inflammatory conditions in HIV-infected individuals

Overview

The literature search identified two case series and 15 case reports of HIV-infected individuals receiving biologic therapy for inflammatory conditions. One further case report published after our original literature search was executed, was also included.³⁰ This represents 37 treatment episodes with 6 different biologic agents encompassing 10 inflammatory conditions (see Table 2). Two case reports describe the same individual patient over 12 years of follow-up.^31,32 Five treatment episodes were identified in a report of Spanish biologic registry data, but no individual clinical details were available for detailed outcomes analysis.⁶ Only for individual patients with diagnoses of psoriasis, psoriatic arthritis and rheumatoid arthritis were more than two cases returned. Of 37 treatment episodes, 33 (89%) entailed use of anti-TNF-a agents.

Table 2.

HIV virological and immunological profiles of individual patients at time of initiation of biologic therapy displayed by clinical indication.

Diagnosis (number of patients)	Age (years)^a	Male	ART at time of biologic agent	Viral suppression at time of biologic agent	Baseline CD4 cell count prior to biologic^b
Dermatology
Pemphigus vulgaris (1)	54	1/1	1/1	1/1	444
Psoriasis (4)	44	4/4	2/4	2/4	432
Gastroenterology
Crohn disease (2)	39	0/2	2/2	2/2	603
Ulcerative colitis (1)	69	1/1	1/1	1/1	357
Rheumatology
Psoriatic arthropathy (8)	45	7/8	5/8	4/8	324 (50–750)
Rheumatoid arthritis (4)	45	3/4	3/4	4/4	666 (530–974)
Reactive arthritis (2)	36	2/2	2/2	2/2	752
Ankylosing spondylitis (1)	34	1/1	1/1	1/1	634
Undifferentiated spondyloarthopathy (1)	50	0/1	1/1	1/1	779
ANCA-associated vasculitis (1)	51	0/1	1/1	1/1	400

Age displayed is age of individual patient. Where study reported two or more patients, the median age is displayed.

Range of CD4 cell counts, if study reported two, or more, patients.

HIV diagnosis and control

For 25 individual patients with adequate clinical details, HIV acquisition preceded onset of inflammatory symptoms in seven, post-dated inflammatory symptoms in nine and in nine other patients the relative timing is unknown. Two individuals started and failed biologic therapy before HIV testing was performed.^33,34 The psoriatic symptoms of both of these patients responded dramatically to ART. Besides different systemic diagnoses, the small group of patients described in the literature may also represent disparate inflammatory syndromes: individuals with recognised pre-existing inflammatory disease,^35,36 occult inflammatory conditions unmasked by both HIV-mediated immunosuppression^33,37 and ART,^31,32,38 and inflammatory symptoms intrinsically related to HIV infection.^33,34,39 It is unknown whether these represent clinical entities that can be directly compared in a study of therapeutic efficacy.

Baseline CD4 lymphocyte cell count and HIV viral load values were available in all but two patients receiving biologic therapy for inflammatory conditions (Table 2). The median CD4 cell count prior to initiation of biologic therapy was 446 cells/µL. Two patients developed inflammatory symptoms with advanced HIV infection and CD4 cell counts of 50 cells/µL or less. Both received only two doses of biologic therapy.^33,37 Twenty patients (20/25, 80%) were established on ART at the time of commencing biologic therapy and 15 of these individuals had an undetectable HIV viral load. Two individuals commenced ART during their treatment with biologic agents. Of those established on ART before or during biologic therapy, the precise regimen was only described in 13 individuals (13/22, 59%). Two ART regimen changes were reported during biologic therapy; however, these were not attributed to any interaction with the biologic agent. No negative immunological or virological outcomes were described across the available literature. However, CD4 cell count and viral load monitoring were inconsistent and often infrequent across the literature.

In a case control study of HIV-tuberculosis co-infected individuals not yet started on ART, 16 study patients received eight doses of etanercept over four weeks in conjunction with routine quadruple anti-tuberculosis therapy.⁴⁰ The 42 CD4 cell count-matched control patients were already receiving oral prednisolone as part of a separate trial. Even in the absence of ART, only a single patient experienced a significant rise in their viral load, leading to cessation of etanercept at 2 weeks.

Efficacy

Treatment duration ranged from induction therapy of three doses to years of maintenance therapy with a median follow-up of 13 months after initiation of biologic therapy. The methods of reporting treatment efficacy were variable. The largest case series of eight patients was designed as a ‘study of safety’ and thus does not include any disease activity scores at baseline or after biologic therapy.³⁸ In the remaining cases, specific disease activity scores were recorded at baseline and at least once after initiation of biologic therapy in only five out of 37 treatment episodes (13.5%). Remission was achieved in all five cases. Where specific disease activity scores were unavailable, a range of informal descriptions were used. Table 3 summarises the response of inflammatory conditions to biologic therapy: ‘unresponsive’ implies failure to respond to therapy from induction, ‘partial’ implies therapy did not reach unspecified therapeutic targets, ‘transient’ implies therapy did reach therapeutic targets but failed to sustain response, and ‘good’ implies therapy reached and sustained therapeutic targets which might include remission (Table 3). Of all treatment episodes, 20/37 (54%) demonstrated a ‘good’ primary response to treatment and only 4/37 (11%) were ‘unresponsive’. Biologic therapy was stopped or switched in 14/37 (38%) treatment episodes. This rate is comparable with non-HIV-infected populations.⁴¹ In these 14 instances, three were prompted by adverse events and 11 by efficacy. Etanercept accounted for 50% (7/14) of the biologic agents stopped. However, Etanercept was also the most common biologic agent used across all conditions (43%, 16/37). Dosing information was available for 11 out of 37 treatment episodes (30%) and largely conformed to international guidelines.

Table 3.

Summary of biologic agent use according to clinical indication.

Diagnosis (total number of patients)	Treatment episodes	Biologics (number of treatment episodes^a)	Median duration of treatment (weeks; range if total patients>2)	Clinical response	Concomitant DMARD
Dermatology
Pemphigus vulgaris (1)	1	R	24	Good	Nil
Psoriasis (4)	8	E (4), A, Al, I, U	30 (12–72)	Good 1/8; partial 2/8; transient 2/8; unknown 2/8; unresponsive 1/8	Corticosteroid
Gastroenterology
Crohn disease (2)	2	I	18	Good 2/2	Corticosteroid
Ulcerative colitis (1)	1	I	20	Partial	Corticosteroid
Rheumatology
Psoriatic arthropathy (8)	13	I (6), E (5), A (2)	96 (90–162)	Good 8/13; partial 3/13; transient 1/13; unresponsive 1/13	HCQ, MTX, corticosteroid, SSZ
Rheumatoid arthritis (4)	5	E (4), I	18 (8–200)	Good 5/5	HCQ, LEF, MTX, corticosteroid, SSZ
Reactive arthritis (2)	2	E, I	44	Good 2/2	Nil
Ankylosing spondylitis (1)	1	E	12	Transient	Nil
Undifferentiated spondyloarthopathy (1)	3	A, E, I	Unknown	Partial 3/3	SSZ
ANCA-associated vasculitis (1)	1	R	One dose	Good	Corticosteroid

DMARD: Disease-modifying antirheumatic drugs; R: Rituximab; E: Etanercept; A: Adalimumab; Al: Alefacept; I: Infliximab; U: Ustekinumab; HCQ: hydroxychloroquine; MTX: methotrexate; SSZ: sulfasalazine.

Number of treatment episodes if n > 1.

Concurrent with biologic agents, 18 patients (18/25, 72%) received other synthetic disease-modifying anti-rheumatic drugs (DMARDs), including steroid therapy (14 patients) and methotrexate (eight patients). Dosing and duration of these agents were very poorly reported.

Adverse events

Analysis of adverse events described in the literature search encompassed those 42 treatment episodes involving treatment of inflammatory conditions (including five patients from the Spanish biologic registry data and a total of 37 treatment episodes described in other papers) and 33 treatment episodes involving treatment of HIV-infected individuals with biologic agents as trial therapy for HIV infection or tuberculosis. For those individuals where the identity of the biologic agent was known, 94% were anti-TNF-a agents (66/70 treatment episodes).

Infectious complications

We identified three infection episodes requiring hospital admission that were attributed to biologic therapy: facial abscess, listeriosis, and ‘frequent polymicrobial infections’.^37,38,42 This equates to three infectious episodes in the cumulative 50 patient–years of all biologic therapies reported in our review. This is similar to HIV-uninfected populations where relative risk of infection is reported for individual biologic agents. In the German Biologics Register RABBIT (Rheumatoide Arthritis: Beobachtung der Biologika-Therapie) study, the reported relative risk of serious infection is 2.70 for all infliximab treatment (20.59 episodes per 100 patient-years).⁴³ By comparison, for synthetic DMARDs in HIV-uninfected patients, registry data suggest that the incidence of serious infection is 5.08 per 100 patient–years.⁴

Given the very small case numbers, our review cannot categorically report any clear association between CD4 cell count at time of initiation of biologic therapy and increased incidence of infectious complications. The patient with ‘polymicrobial infections’ had a baseline CD4 cell count of 50 cells/µL. No clinical detail is provided on the nature of these infections. However, the only other patient with a CD4 cell count less than 200 cells/µL among patients treated for inflammatory conditions, with 29 cells/µL, did not develop any infectious sequelae.

Combined corticosteroid and DMARD use with anti-TNF therapy is associated with increased risk of infectious complications in HIV-uninfected cohorts: an odds ratio (OR) of 14.5 for combined therapy compared with 2.9 for anti-TNF monotherapy in HIV-negative patients.⁴⁴ All four patients identified in our review with any infectious complications attributed to biologic therapy, received concomitant corticosteroid therapy. However, seven other patients in our review who also received concurrent corticosteroid therapy developed no infectious complications. Corticosteroid dosing was not consistently reported.

Age greater than 50 years is associated with a threefold increased risk for serious infections in patients receiving anti-TNF therapies.⁴⁴ Advancing age is an independent risk factor for Listeria monocytogenes infection in any setting.⁴⁵ The case of neuroinvasive listeriosis occurred in a patient aged 69 years.⁴²

In HIV-uninfected patients, the highest incidence of infectious complications occurs within six months of starting biologic therapy.⁴⁶ All infectious complications occurred within six months of initiating biologic therapy in our review. There is little discussion of antibiotic prophylaxis in the cases returned. However, one individual received dapsone prophylaxis following pneumocystis pneumonia, despite a well-preserved CD4 cell count at the time of biologic therapy initiation.³⁸ In the trial of etanercept as adjuvant therapy for tuberculosis as described above, two patients, with a mean CD4 cell count of 394 cells/µL, were withdrawn after four doses of etanercept owing to increasing burden of acid fast bacilli in sputum samples.⁴⁰ We did not consider this evidence of a serious adverse event nor clearly attributable to the biologic therapy. In this study, there were no increased infectious complications in those 16 HIV-infected individuals receiving etanercept compared with the 42 HIV-infected control patients.

Non-infectious complications

Allergic reactions, all within the first four doses of therapy, were experienced by three HIV-infected individuals.^35,38,47 Anaemia and acute anterior uveitis have been described as adverse events but no clinical detail was provided.^36,38 In a recent meta-analysis of HIV-uninfected patients, biologic therapy was associated with a small increased risk of melanoma but not other malignancy. No malignant complications were identified in our systematic review. Two HIV-infected patients died during the course of biologic therapy. Both deaths occurred in patients receiving etanercept as trial therapy for non-inflammatory conditions (HIV and tuberculosis, respectively) and the cause of death, mesenteric atherosclerosis and pulmonary embolism were not deemed to be related directly to anti-TNF-a therapy.^40,48

Discussion

Across all organ systems, autoimmune inflammatory pathology is thought to be common in HIV-infected individuals. However, the understanding of the natural history of these diverse conditions in the setting of HIV infection, as well as long-term follow-up of their clinical manifestations is limited. Even for non-biologic treatment of HIV-infected patients living with inflammatory conditions, there are only limited efficacy and safety data. Biologic therapies have already transformed the lives of HIV-uninfected patients with severe autoimmune conditions. For HIV-uninfected patients, these agents are increasingly used by clinicians and may in the future be ‘gold standard’ for first-line therapy, irrespective of disease severity. Therefore, both current and future clinical parity for HIV-infected individuals diagnosed with inflammatory diseases warrants closer and more rigorous consideration of biologic therapy use.

Unfortunately, the available literature that specifically addresses the use of biologic agents in the treatment of HIV-infected individuals with inflammatory conditions is of poor quality. For some specific inflammatory diagnoses, such as ulcerative colitis, available data are limited to single patient case reports. Psoriasis represents the most studied condition but only eight treatment episodes were identified in the literature. Although detailed disease scoring systems were often absent, our review suggests that treatment responses were comparable to HIV-uninfected patients receiving biologic therapy. Publication bias towards positive outcomes is a legitimate concern given the small sample. Unsurprisingly, there are no ‘control’ data for inflammatory outcomes in HIV-infected individuals. Uncertainty also remains in terms of HIV control during biologic therapy. A single case-control study examining the use of biologic agents for treatment of HIV-tuberculosis co-infection in patients not receiving ART suggested that etanercept did not adversely affect HIV control. As there are no equivalent studies for individuals established on ART, suggesting biologic therapies do not adversely interact with ART currently lacks an evidence-base. However, no negative effects on ART therapy were identified in our review.

The higher quality literature pertaining to the use of biologics for haematological indications is limited, almost exclusively to rituximab, whereas guidelines for treatment of severe inflammatory conditions in HIV-uninfected groups is predicated largely on use of anti-TNF-a agents. Patients with haematological malignancy and lymphoproliferative disorders may also represent a relatively more immunocompromised cohort of patients and who receive concurrent chemotherapy, confounding direct comparison with patients receiving the same agents for inflammatory indications.

In summary, our systematic review highlights a paucity of good quality data on use of biologic therapies to treat inflammatory conditions in HIV-infected individuals. All evidence reviewed that addressed this clinical area directly rated very low quality according to the GRADE system.⁴⁹ Due to this major limitation, the review of a cross section of common inflammatory conditions and agents, we cannot conclude or exclude comparable efficacy and safety of biologic therapies between HIV-infected and -uninfected populations. However, we feel that available data support inclusion of HIV-infected individuals with well-controlled HIV infection in future studies of biologic therapy. There remains a broader need to study the diagnosis, natural history, and management of inflammatory conditions in HIV-infected populations. Rigorous and formal prospective data collection of this burgeoning group of patients would represent a key first step to this better understanding (Table 4). This may lead to care equality for HIV-infected patients suffering from inflammatory conditions who might benefit from biologic therapies that continue to transform the lives of HIV-uninfected individuals.

Table 4.

Future research questions.

Areas of clinical need	Future directions
Natural history of inflammatory conditions and validation of disease activity scores in HIV-infected patients on and off ART	International multicentre prospective study
Understanding of the efficacy and dosing of non-biologic DMARDS in HIV-infected patients on and off ART	International multicentre observational study; randomised control trial
Understanding of the efficacy of biologics in HIV-infected patients on and off ART	Multicentre randomised control trial
Understanding of the safety of biologics in HIV-infected patients (including biologic-ART interactions)	HIV-infected population dedicated database; randomised control trial

ART: anti-retroviral therapy; DMARD: Disease modifying anti-rheumatic drugs.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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