Optimal timing for antiretroviral therapy initiation in patients with HIV infection and concurrent cryptococcal meningitis

  • Review
  • Intervention

Authors


Abstract

Background

Currently, initiation of antiretroviral therapy (ART) in most patients with human immunodeficiency virus (HIV) infection is based on the CD4-positive-t-lymphocyte count. However, the point during the course of HIV infection at which ART should be initiated in patients with concurrent cryptococcal meningitis remains unclear. The aim of this systematic review was to summarise the evidence on the optimal timing of ART initiation in patients with cryptococcal meningitis for use in clinical practice and guideline development.

Objectives

To compare the clinical and immunologic outcomes for early initiation ART (less than four weeks after starting antifungal treatment) versus later initiation of HAART (four weeks or more after starting antifungal treatment) in HIV-positive patients with concurrent cryptococcal meningitis.

Search methods

We searched the following databases from January 1980 to February 2011: PubMed, EMBASE, and WHO International Clinical Trials Registry Platform, AEGIS database for conference abstracts, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews. A total of 35 full text articles were identified and supplemented by a bibliographic search. We contacted researchers and relevant organizations and checked reference lists of all included studies.

Selection criteria

Randomized controlled trials that compared the effect of ART (consisting of three drug combinations) initiated early or delayed in HIV patients with cryptococcal meningitis.

Data collection and analysis

Two review authors independently assessed study eligibility, extracted data, and graded methodological quality. Data extraction and methodological quality were checked by a third author who resolved differences when these arose. Where clinically meaningful, we performed a meta-analysis of dichotomous outcomes using the relative risk (RR) and report the 95% confidence intervals (95% CIs).

Main results

Two eligible randomized controlled trials were included (N = 89). In our pooled analysis, we combined the clinical data for both trials comparing early initiation ART versus delayed initiation of ART. There was no statistically significant difference in mortality (RR=1.40, 95% CI [0.42, 4.68]) in the group with early initiation of ART compared to the group with delayed initiation of ART.  

Authors' conclusions

This systematic review shows that there is insufficient evidence in support of either early or late initiation of ART. For the moment, because of the high risk of immune reconstitution syndrome in patients with cryptococcal meningitis, we recommend that ART initiation should be delayed until there is evidence of a sustained clinical response to antifungal therapy. However, large studies with appropriate comparison groups, and adequate follow-up are warranted to provide the evidence base for effective decision making.

Résumé scientifique

Moment optimal pour le démarrage d'un traitement antirétroviral chez les patients atteints d'une infection par le VIH et d'une méningite cryptococcique concomitante

Contexte

Actuellement, le démarrage du traitement antirétroviral (TAR) chez la plupart des patients atteints d'une infection par le virus de l'immunodéficience humaine (VIH) est basé sur la numération des lymphocytes T-CD4+. Toutefois, le point au cours de l'infection par le VIH auquel le TAR devrait être démarré chez les patients atteints d'une méningite cryptococcique concomitante reste indéterminé. Le but de cette revue systématique était de résumer les preuves en faveur du moment optimal du démarrage du TAR chez les patients atteints de méningite cryptococcique pour une utilisation en pratique clinique et l'émission de recommandations.

Objectifs

Comparer les résultats cliniques et immunologiques en faveur d'un démarrage précoce du TAR (moins de quatre semaines après le début du traitement antifongique) à un démarrage différé du TAHA (traitement antirétroviral hautement actif) (quatre semaines ou plus après le début du traitement antifongique) chez les patients séropositifs atteints d'une méningite cryptococcique concomitante.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans les bases de données suivantes de janvier 1980 à février 2011 : PubMed, EMBASE, et le système d'enregistrement international des essais cliniques de l'OMS, la base AEGIS des actes de conférences, le registre Cochrane des essais contrôlés (CENTRAL), et la base des revues systématiques Cochrane. Un total de 35 articles en texte intégral a été identifié et complété par une recherche bibliographique. Nous avons contacté des chercheurs et des organismes pertinents, et vérifié les listes bibliographiques de toutes les études incluses.

Critères de sélection

Les essais contrôlés randomisés qui comparaient l'effet du TAR (consistant en trois combinaisons de médicaments) selon un démarrage précoce ou différé chez les patients atteints du VIH présentant une méningite cryptococcique.

Recueil et analyse des données

Deux auteurs de la revue ont, de manière indépendante, évalué l’admissibilité et la qualité méthodologique des études et extrait les données. L'extraction des données et la qualité méthodologique ont été vérifiées par un troisième auteur qui a résolu les différences, le cas échéant. Lorsque cela était cliniquement significatif, nous avons effectué une méta-analyse des critères de jugement dichotomiques au moyen du risque relatif (RR) et avons rapporté les intervalles de confiance (IC) à 95 % (IC à 95 %).

Résultats principaux

Deux essais contrôlés randomisés éligibles ont été inclus (N = 89). Dans notre analyse groupée, nous avons combiné les données cliniques des deux essais comparant le démarrage précoce du TAR à un démarrage différé du TAR. Il n'y avait aucune différence statistiquement significative en termes de mortalité (RR = 1,40, IC à 95 % [0,42, 4,68]) dans le groupe de démarrage précoce du TAR comparé au groupe de démarrage différé du TAR.

Conclusions des auteurs

Cette revue systématique montre que les preuves sont insuffisantes pour soutenir soit le démarrage précoce soit le démarrage différé du TAR. Pour le moment, en raison du risque élevé de syndrome de reconstitution immunitaire chez les patients atteints de méningite cryptococcique, nous recommandons que le démarrage du TAR soit différé jusqu'à ce que l'on dispose de preuves d'une réponse clinique soutenue au traitement antifongique. Toutefois, des études à grande échelle avec des groupes de comparaison appropriés, et une période de suivi suffisante sont justifiées pour constituer la base des preuves pour une prise de décision efficace.

Plain language summary

When is the best time to start antiretroviral therapy in people with HIV, who also have cryptococcal disease infection of the brain and spinal cord?

Antiretroviral therapy (ART) has been shown to be effective in slowing down the progression of AIDS and in reducing HIV-related illnesses and death. Currently, this therapy is given based on a patient’s CD4 cell count (the body's defense system). An HIV-infected individual whose meninges (the membranes covering the brain and spinal cord) are also infected by a fungus called Cryptococcus neoformans is considered very sick with his/her immune system severely weakened, and therefore will require ART.

At the moment, the best time to start ART in these patients is unclear. The objective of this review is to assess the evidence for the optimal time to initiate ART in people with HIV infection, who also have cryptococcal disease infection of the membranes covering their brain and spinal cord (meningitis).  

The authors reviewed two trials which involved 89 participants. Both studies compared the effect of early ART initiation within the first month after starting treatment for fungi infection (Cryptococcus neoformans) to delayed ART initiation starting from the second month onwards. Results showed that we still lack enough evidence to determine whether early or late initiation of ART is best. However, the authors recommend that the initiation of ART in people with HIV infection who also have cryptococcal disease of the brain should be delayed until after some clinical improvement of the fungal disease is noted.

Résumé simplifié

Quel est le meilleur moment pour démarrer le traitement antirétroviral chez les personnes atteintes du VIH, qui présentent également une infection par cryptococcus du cerveau et de la moelle épinière ?

Le traitement antirétroviral (TAR) s'avère être efficace pour ralentir la progression du SIDA et pour réduire les maladies liées au VIH et la mortalité. Actuellement, ce traitement est administré sur la base de la numération lymphocytaire CD4 du patient (le système immunitaire de l'organisme). Un individu infecté par le VIH dont les méninges (les membranes recouvrant le cerveau et la moelle épinière) sont également infectées par un champignon appelé Cryptococcus neoformans est considéré être très malade puisque son système immunitaire est gravement affaibli, et nécessitera par conséquent un TAR.

À l'heure actuelle, le meilleur moment pour démarrer un TAR chez ces patients est indéterminé. L'objectif de cette revue est d'évaluer les preuves en faveur du moment optimal pour démarrer un TAR chez les personnes atteintes d'une infection par le VIH, qui présentent également une infection par cryptococcus des membranes recouvrant leur cerveau et moelle épinière (méningite).

Les auteurs ont examiné deux essais ayant totalisé 89 participants. Les deux études ont comparé l'effet du démarrage précoce du TAR au cours du premier mois suivant le début du traitement contre les infections fongiques (Cryptococcus neoformans) à un démarrage différé du TAR commençant à compter du deuxième mois. Les résultats ont montré que nous ne disposons toujours pas de preuves suffisantes pour déterminer si un démarrage précoce ou différé du TAR est meilleur. Cependant, les auteurs recommandent que le démarrage du TAR chez les personnes atteintes d'une infection par le VIH, qui présentent également une maladie par cryptococcus du cerveau, soit différé jusqu'à ce qu'une certaine amélioration clinique de la mycose soit notée.

Notes de traduction

Traduit par: French Cochrane Centre 1st March, 2013
Traduction financée par: Pour la France : Ministère de la Santé. Pour le Canada : Instituts de recherche en santé du Canada, ministère de la Santé du Québec, Fonds de recherche de Québec-Santé et Institut national d'excellence en santé et en services sociaux.

Summary of findings(Explanation)

Summary of findings for the main comparison. Early ART initiation versus delayed ART initiation
Early ART initiation versus delayed ART initiation for antiretroviral therapy initiation in patients with HIV infection and concurrent cryptococcal meningitis
Patient or population: patients with antiretroviral therapy initiation in patients with HIV infection and concurrent cryptococcal meningitis
Settings: South Africa, USA, Puerto Rico, Zimbabwe
Intervention: Early ART initiation versus delayed ART initiation
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
 ControlEarly ART initiation versus delayed ART initiation   

IRIS (not measured): While Zolopa et al reports confirmed IRIS in 20 cases, the authors did not report the number of these cases that were due to cryptococcosis. Makadzange et al did not report IRIS

Severe adverse events (not measured): Zolopa did not differentiate IRIS or Severe adverse events among different baseline opportunistic infections. Makadzange et al did not report Severe adverse events.

DeathStudy populationRR 1.4
(0.42 to 4.68)
89
(2)
++OO
Low

Risk of bias (serious): The two included trials were open labelled. Both had >10% lost to follow up. In the trial by Makadzange et al, 42% of eligible patients could not be randomised. Futhermore, different treatment regimens for cryptococcal meningitis and different follow-up times (2 years in Makadzange et al and 48 weeks in Zolopa et al) were used. In delayed arms, ART was introduced at week 10 in Makadzange and weeks 6-12 in Zolopa.

Inconsistency (serious): Trials showed different results

Imprecision (serious): Low number of total events (37 for mortality, 2 for AIDS progression).

Other considerations: The trial by Makadzange et al was terminated early by DSMC.

292 per 1000409 per 1000
(123 to 1000)
409 per 1000
(123 to 1000)
Medium risk population
276 per 1000386 per 1000
(116 to 1000)
386 per 1000
(116 to 1000)
386 per 1000
(116 to 1000)
AIDS progressionStudy populationRR 1.63
(0.84 to 3.16)
89
(2)
+OOO
Very Low

Risk of bias ( very serious): Zolopa: open label study, 13% withdrew and were lost to follow up. Study not powered for CM endpoint but any new OI or death.

Imprecision (serious): Low number of total events (37 for mortality, 2 for AIDS progression)

Other considerations: The trial by Makadzange et al was terminated early by DSMC

Risk of bias ( very serious): Zolopa: open label study, 13% withdrew and were lost to follow up. Study not powered for CM endpoint but any new OI or death.

Imprecision (serious): Low number of total events (37 for mortality, 2 for AIDS progression)

Other considerations: The trial by Makadzange et al was terminated early by DSMC

188 per 1000306 per 1000
(158 to 594)
306 per 1000
(158 to 594)
306 per 1000
(158 to 594)
Medium risk population
177 per 1000289 per 1000
(149 to 559)
289 per 1000
(149 to 559)
289 per 1000
(149 to 559)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
       

Background

The human immunodeficiency virus (HIV) invades the human immune system and impairs its function leaving it susceptible to other infections and some cancers (WHO 2012). Untreated infection with HIV leads to Acquire Immune Deficiency Syndome (AIDS). HIV infection is one of the world's leading causes of death, and is responsible for more that 25 million deaths in the past 30 years (WHO 2012). It is diagnosed using highly sensitive HIV antibody screening tests and confirmed with more specific tests such as immune-blotting and polymerase chain reactions (Van Heuverswyn 2006). Despite a reduction in the number of new infections over the past decade, the number of people living with HIV has continued to rise due to the life-prolonging effects of antiretroviral therapy (ART). At the end of 2009, the total number of people living with HIV stood at 33.4 million, of which 2.7 million were newly infected cases (WHO 2009). 

In the absence of appropriate therapy, people living with HIV may develop a number of serious conditions including cryptococcal meningitis (CM), tuberculosis and Kaposi's sarcoma (WHO 2012). CM is a leading cause of death in people with AIDS (Jarvis 2008).

Description of the condition

Cryptococcal meningitis (CM) usually occurs in people with advanced stages of HIV infection, and is considered to be an AIDS-defining condition (WHO 2007, CDC 1992). CM is a fungal infection caused by one of four serotypes of Cryptococcus neoformans (A, B, C or D). In people immunocompromised by HIV, the majority of infections are caused by serotype D, whereas serotypes B and C are more commonly identified in other immunocompetent populations. Cryptococcal meningitis is often suspected when people with HIV manifest signs of central nervous system (CNS) involvement like hallucinations, fever, headache, stiff neck or a change in their mental status (Kauffman 2007). The diagnosis is initially made by India ink staining of cerebrospinal fluid or cryptococcal polysaccharide antigen (CRAG) test, which is more accurate (MacDougall 2007; Pongsai 2010). Rapid diagnosis and adequate treatment are required to prevent the complications of cryptococcal meningitis which include seizures, cerebral infarction, hydrocephalus and elevated cerebrospinal fluid pressure. The use of ART is associated with a lower incidence of cryptococcosis, whereas, in regions with uncontrolled HIV infection and limited access to ART, such as Africa and Asia, the incidence and mortality from cryptococcosis are extremely high (Chayakulkeeree 2006).

Description of the intervention

The treatment of cryptococcal meningitis is usually initiated with a combination of two antifungal drugs for at least two weeks followed by eight weeks of a single antifungal drug (Sloan 2006). Amphotericin-B combined with flucytosine or fluconazole is recommended as the initial standard treatment option. In settings where amphotericin B is not available, regimens containing fluconazole combined with flucytosine, or high-dose fluconazole monotherapy are alternative options (WHO 2011). A regimen containing oral fluconazole is the recommended treatment during the eight-week consolidation treatment phase and the subsequent maintenance treatment (WHO 2011). ART is indicated in this group of patients within four to six weeks after initiation of antifungal treatment. However, the optimal timing for initiation of ART in people with CM has not yet been established (Jarvis 2007). In HIV-positive patients who successfully complete treatment for acute cryptococcal meningitis, fluconazole is used for maintenance therapy for life or until there is consistent response to ART.

How the intervention might work

An adequate response to antiretroviral treatment is defined as a consistent rise in CD4 count of more than 199 cells per microlitre and undetectable HIV-RNA for a minimum of three months (Saag 1999, WHO 2007). Initiation of ART improves immune responses to cryptococcosis in a majority of HIV patients but about one-third of these patients may develop an inflammatory disease within a few months of treatment initiation (Singh 2005). This exaggerated inflammatory response is known as immune reconstitution inflammatory syndrome (IRIS). To reduce the probability of developing IRIS, some health care providers prefer to delay the initiation of ART until the completion of antifungal induction therapy (Skiest 2005). While delayed initiation might reduce the risk of IRIS, it is not clear whether it is more effective than early therapy.

Why it is important to do this review

The optimal timing for initiation of ART in HIV-positive patients with concurrent CM is not known (NIH 2008). A systematic review of randomized controlled trials (RCTs) to compare the effects of early versus delayed initiation of ART will help health care providers to make evidence-based decisions in the management of CM.

Objectives

To compare the clinical and immunological outcomes of early initiation of ART (less than four weeks after starting antifungal treatment) versus delayed initiation (four weeks or more after starting antifungal treatment) in HIV-positive patients with concurrent cryptococcal meningitis.

Methods

Criteria for considering studies for this review

Types of studies

We included randomized-controlled clinical trials that compared early versus delayed initiation of ART in patients with CM.

Types of participants

Trials involving HIV-infected individuals with paraclinical evidence of cryptococcal meningitis

Types of interventions

The comparisons groups included were:

  1. Early initiation of ART: ART initiated within four weeks of starting antifungal treatment.

  2. Delayed initiation of ART: ART initiated at least four weeks of starting antifungal treatment.

All combinations of triple ART and antifungal drugs (single or combined) were acceptable if both arms of the trial differed in timing of initiation of ART.

Types of outcome measures

Primary outcomes

1.   All-cause mortality (all-cause mortality)

2.   Response to ART as measured by:

  • Proportion of patients progressing to potentially life-threatening CNS disease.

  • Proportion with disappearance of cryptococcal polysaccharide antigen (CRAG) in CSF.

  • Proportion of patients achieving and maintaining an undetectable viral load, as defined by the trial investigators.

  • Time-to-event of new HIV-related events (death or AIDS-defining illness).

  • Immunologic response - mean relative/absolute change in the CD4-positive-T-lymphocyte cell count from the baseline).

  • Virologic response - mean relative/absolute change in the HIV-RNA levels from the baseline.

Secondary outcomes
  1. Development of IRIS.

  2. Development of ART resistance.

  3. Proportion of patients discontinuing or switching ART due to virologic failure, as defined by the trial investigators.

  4. Proportion of patients remaining on ART and antifungal therapy as originally assigned at the end of the trial.

  5. Quality of life indicators as reported in the studies.

  6. Serious adverse events, including deterioration of serum electrolytes, renal function, and bone marrow function, graded using the Adverse Event Toxicity Scale.

Search methods for identification of studies

See Figure 1.

Figure 1.

Flow diagram

Electronic searches

See: HIV/AIDS Collaborative Review Group search strategy.

We performed an exhaustive search that was based on the HIV/AIDS Collaborative Review Group search strategy with the assistance of the HIV/AIDS Review Group Trials Search Co-ordinator. Full details of the Cochrane HIV/AIDS Review Group methods and the journals hand-searched are published in The Cochrane Library in the section on Collaborative Review Groups (http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/HIV/frame.html).

We searched the following electronic databases:

1. The Cochrane Library (Issue 1, 2010)

2. The Cochrane Central Register of Controlled Trials (CENTRAL) from 1980 to February 2011

3. Excerpta Medica Database (EMBASE) from 1980 to February 2011

4. MEDLINE from 1980 to February 2011

and

5. The WHO International Clinical Trials Registry Platform (ICTRP) from 1980 to February 2011

See Appendix 1 for all search strategies.

These databases were searched for randomized controlled trials of ART plus antifungal treatment in HIV-infected patients with concurrent cryptococcal meningitis, using standardised methodological filters for randomized controlled trials developed by the Cochrane Collaboration (Higgins 2009) in combination with terms specific to ART, antifungal drugs and cryptococcal meningitis.

Searching other resources

We checked the bibliographic references of identified randomized clinical trials, textbooks, review articles, and meta-analyses in order to find randomized clinical trials that were not identified by the electronic searches. We also identified studies from conference databases such as the NLM Gateway and ongoing trials by reviewing the reference lists and contacting the principal authors of the identified trials. All studies irrespective of their publication status (published, unpublished, in press, and in progress) or language of the publication were considered for inclusion.

Data collection and analysis

We carried out a meta-analysis of the results from methodologically and clinically comparable trials. The analyses were performed using Review Manager (Revman 2011) statistical software. BN,SK and LM entered the data and conducted the analyses independently. Any disagreements were resolved by discussion with a fourth review author (EJK). All the authors reviewed the results and their interpretation.

Selection of studies

Two authors (EJK and SK) independently assessed the trials for inclusion in the review. The third author (BN) reviewed the excluded studies independently to ensure accuracy. EJK and BN read the titles, abstracts, and descriptor terms of all the studies retrieved from the electronic searches to identify the eligible trials. Full text articles were obtained for all potentially eligible studies. We also obtained full-text articles if there was any uncertainty as to the eligibility of a particular citation. BN and EJK independently reviewed the full-text articles for relevance based on the study design, types of participants, interventions and outcome measures. Any differences were resolved by discussions with LM and EJK.

Data extraction and management

BN,SK and LM independently extracted data onto a standardised data extraction form. The following data were extracted with respect to antiretroviral treatment initiation in HIV-positive patients with cryptococcal meningitis:

  1. Relevant baseline characteristics including CD4-positive-T-lymphocyte count and viral load

  2. Drug combinations and co-interventions

  3. Survival data during the study period

  4. Serious adverse events, including deterioration of CNS function

  5. Development of viral resistance to the drug used

  6. Type of ART and antifungal treatment

  7. Responses to ART

  8. Proportion of patients remaining on treatment or either discontinuing or switching ART due to virologic failure

Assessment of risk of bias in included studies

The methodological quality of the trials was assessed based on the generation of allocation sequence, allocation concealment, blinding (participants, personnel and outcome assessor), incomplete outcome data, selective outcome reporting, and other sources of bias. These quality components were classified in accordance with the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2009) as follows:

1. Sequence generation

  • Adequate: investigators described a random component in the sequence generation process such as the use of a random number table, coin tossing, shuffling cards or envelopes etc.

  • Inadequate: investigators described a non-random component in the sequence generation process such as the use of odd or even dates of birth, algorithm based on the day/date of birth, hospital or clinic record number.

  • Unclear: insufficient information to permit judgment of the sequence generation process.

2. Allocation concealment

  • Adequate: participants and the investigators enrolling participants cannot foresee assignment (e.g. central allocation; or sequentially numbered, opaque, sealed envelopes).

  • Inadequate: participants and investigators enrolling participants can foresee upcoming assignment (e.g. an open random allocation schedule (e.g. a list of random numbers); or envelopes were unsealed or non opaque or not sequentially numbered).

  • Unclear: insufficient information to permit judgment of the allocation concealment or the method not described.

3. Blinding

  • Adequate: blinding of the participants, key study personnel and outcome assessor; unlikely that the blinding could have been broken or lack of blinding unlikely to introduce bias. No blinding in the situation where non-blinding is not likely to introduce bias.

  • Inadequate: no blinding, incomplete blinding and the outcome is likely to be influenced by lack of blinding.

  • Unclear: insufficient information to permit judgment of adequacy or otherwise of the blinding.

4. Incomplete outcome data

  • Adequate: no missing outcome data, reasons for missing outcome data unlikely to be related to true outcome, or missing outcome data balanced in number across groups.

  • Inadequate: reason for missing outcome data likely to be related to true outcome, with either imbalance in number across groups or reasons for missing data.

  • Unclear: insufficient reporting of attrition or exclusions.

5. Selective Reporting

  • Adequate: a protocol is available which clearly states the primary outcome as the same as in the final trial report.

  • Inadequate: the primary outcome differs between the protocol and final trial report.

  • Unclear: no trial protocol is available or there is insufficient reporting to determine if selective reporting is present.

6. Other forms of bias

  • Adequate: there is no evidence of bias from other sources.

  • Inadequate: there is potential bias present from other sources (e.g. early stopping of trial, fraudulent activity, extreme baseline imbalance or bias related to specific study design).

  • Unclear: insufficient information to permit judgment of adequacy or otherwise of other forms of bias.

Assessment of Quality of Evidence Across Studies

We assessed the quality of the body of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (Guyatt 2008), defining the quality of evidence for each outcome as the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest (Higgins 2009). The quality rating across studies has four levels: high, moderate, low and very low. Randomized controlled trials are categorised as high quality but can be downgraded. Factors that decrease the quality of evidence include limitations in design, indirectness of evidence, unexplained heterogeneity or inconsistency of results, imprecision of results, or high probability of publication bias (Guyatt 2008). We used the GRADEpro software to perform our analyses (GradePro 2008).

Measures of treatment effect

Outcome measures for binary data were calculated as a relative risk (RR) with 95% confidence intervals (CI). Continuous data (e.g. CD4-positive-T-lymphocyte cell counts, HIV-RNA viral loads) were calculated using mean differences (MD) and standard deviations (SD). The number needed to treat (NNT) was calculated as 1/((1-relative risk)*control group event rate), wherever applicable.

Dealing with missing data

During data extraction the authors of the studies with missing or unclear data were contacted. Missing data was also sought from secondary publications of the same study.

Assessment of heterogeneity

We assessed clinical heterogeneity for all included studies. If they were sufficiently similar to pool we tested for statistical heterogeneity using the Chi-square test for statistical homogeneity with level of statistical significance set at alpha= 0.1. The impact of any statistical heterogeneity was quantified using the I² statistic (Higgins 2009).

Assessment of reporting biases

We intended to assess publication bias by looking at the funnel plot asymmetry (Egger 1997). However, due to the limited number of included studies, we were unable to carry out the same.

Data synthesis

For data analysis, we planned to report the results of the fixed effects model (DeMets 1987) but for outcomes with significant heterogeneity. When significant heterogeneity was found we reported the results of the random effects model (DerSimonian 1986) and explored potential sources of heterogeneity. Sources of clinical heterogeneity in our meta-analyses include (1) age differences in the inclusion criteria for the two studies - one study included patients aged >13 years and another included patients ≥18 years (2) one study was conducted in many centers and another was just in one center. A random-effect model was used and interpretation was done according to the implications of the subgroup and heterogeneity analyses.

Subgroup analysis and investigation of heterogeneity

We had planned to perform subgroup analysis with:

  • Age of patients - adolescents compared to adults.

  • Treatment naive compared to relapses or non-responders.

  • Category of anti-fungal or antiretroviral therapy used: Amphotericine, Flucytosine, Fluconazole, Itraconazole or ART combinations.

  • Trials with low risk of bias compared to trials with unclear or high risk of bias.

However, due to the limited number of studies found and the lack of data, we were unable to carry out these subgroup analyses.

Sensitivity analysis

Trials in which allocation concealment was unclear or inadequate were excluded from meta-analysis and the effect of this exclusion on the overall results assessed. In addition, a 'worst-case scenario' analysis was performed in which participants with missing data were considered as treatment failures.

Results

Description of studies

See "Characteristics of included studies" and "Characteristics of excluded studies".

Results of the search

Our search retrieved 221 studies

of which 35 studies were potentially eligible for inclusion. After screening the full text articles, only two were included (Makadzange 2010; Zolopa 2009).        

Included studies

The first trial (Makadzange 2010) was an open label trial conducted in Harare, Zimbabwe. It included 54 HIV-infected adults with CM confirmed by India ink examination or the CRAG test. The patients were randomized to either the early intervention group (ART initiated by 72 hours after CM diagnosis) or the delayed intervention group (ART initiated after 10 weeks of fluconazole therapy). All participants were started on a daily dose of fluconazole 800mg at the time of CM diagnosis. After 10 weeks, fluconazole was reduced to a prophylactic dose of 200mg/d. Cases of treatment failure continued or resumed fluconazole at 800 mg/d. The patients were seen for follow-up at regular intervals for 9 months. The primary outcome was all cause mortality. The secondary outcomes were serious adverse effects including IRIS, tuberculosis, severe anaemia, jaundice, gastroenteritis, pneumonia, cerebrovascular accidents, desquamating rash, deterioration of serum electrolytes, renal function, and bone marrow function.

The second trial (Zolopa 2009) was a Multicentre trial with 39 sites in the US and Puerto Rico and one site in Johannesburg, South Africa. It included 283 HIV-infected patients with acute AIDS-related opportunistic infections (OI) out of which 35 (12%) had CM confirmed by India ink examination or CRAG test. The patients were randomized to either the early intervention group (ART initiated by 48 hours after enrolment) or the delayed intervention group (ART initiated between weeks 4 and 32 for study-provided ART and between weeks 6 and 12 for regular ART). All subjects in both arms were followed up for 48 weeks.The primary endpoint of the study was a 3-level ordered categorical variable: alive without AIDS progression and with HIV viral load <50 copies/mL (best outcome); alive without AIDS progression and with detectable HIV viral load (>50 copies/mL at 48 weeks; and AIDS progression or death (worst outcome) at any time.The secondary outcomes were death/AIDS progression; virological response; CD4-positive-T-lymphocyte count at 48 weeks; safety and tolerability of ART; hospitalizations; ART adherence and IRIS.

Ongoing trial

The “Trial for the Optimal Timing of HIV Therapy After Cryptococcal Meningitis (COAT)” (NCT01075152) was stopped in April 2012 by an independent data and safety monitoring board (DSMB), after  reviewing interim study data from 174 participants (NIAID 2012). Of that number, 87 participants were assigned to receive early ART compared to the 87 participants assigned to receive delayed HIV treatment.  The DSMB recommended that no new participants be enrolled because it found higher mortality (42.5%) in participants assigned to the early ART arm. In the standard care arm, mortality was 27.6%.

The DSMB found that in 174 participants, those assigned to early ART were about 1.7 times more likely to die at any one point compared to participants receiving delayed ART. The difference in mortality was more apparent in participants with a Glasgow Coma Scale (GCS) of <15. This was especially the case between 8-30 days after randomization. The trial showed no evidence of benefit of early ART in participants with normal mental status at enrolment. The DSMB determined that the trial would be unlikely to show a significant survival benefit through early ART, and recommended that enrolment be stopped. Clinical follow-up is still ongoing for some of the trial’s secondary endpoints, including (at this writing) survival at 46 weeks and cryptococcal IRIS at 46 weeks.

Efforts to obtain more detailed trial data for this review were unsuccessful. We anticipate updating this review when these data are released, probably in mid-2013.

Excluded studies

Twenty four studies were excluded from this review. Six of them did not compare timing of initiation of ART (Bicanic 2008; Chetchotisakd 2004; Khawcharoenporn 2007; Manosuthi 2009; Pappas 2009; Vibhagool 2003). Eighteen were not RCTs (Bicanic 2007; Bicanic 2010; Boulware 2010a; Carbonara 2009; Chimalizeni 2010; Chottanapund 2007; Grant 2010; Grant 2010a; King 2002; Lawn 2011; Manfredi 1999; Martinez 2000; Müller 2010; Peters 1994; Portegies 2004; Saez 2006; Seddon 2009; Sloan 2008).

See the characteristics of excluded studies table (Characteristics of excluded studies).

Risk of bias in included studies

See  Figure 2 and Figure 3 for a graphical representation of the risk of bias in both trials.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

In both the included trials, computer generated random sequence was used, and allocation concealment was done centrally. In Makadzange 2010, 42% of eligible patients could not be randomized, and baseline data is not reported for all participants. The risk of selection bias in this trial is high. In Zolopa 2009, we judged both random generation and allocation concealment to be adequate and not likely to introduce bias.

Blinding

Both of the included studies were open label studies, so the risk of performance bias and detection bias is high. The outcome assessors in Zolopa 2009 were not blinded. Makadzange 2010 reported on blinding of outcome assessors only for IRIS.

Incomplete outcome data

Some outcome data was not reported for the Makadzange trial (Makadzange 2010). Participants for whom the outcomes were unknown were censored. It is unclear how censoring was done.

Selective reporting

There was no reporting bias in both the included studies. Both of them (Makadzange 2010; Zolopa 2009) reported the outcomes stated in their registered protocols ( NCT00830856 and NCT00055120 respectively).

Other potential sources of bias

Zolopa 2009 appears to be free of other sources of bias. On the other hand, the Makadzange 2010 trial was stopped early by its DSMB due to excess mortality in one arm. This trial manuscript (Makadzange 2010) also had some reporting discrepancies which hampered our appreciation of mortality, censoring and intention-to-treat. These discrepancies have been highlighted in other papers (Boulware 2010b). In addition, some baseline data were missing and their potential effect on randomization is unclear.

Effects of interventions

See: Summary of findings for the main comparison Early ART initiation versus delayed ART initiation

Many of the primary and secondary outcomes we sought were not reported in the included studies. Both trials (Makadzange 2010; Zolopa 2009) compared early initiation of ART to delayed initiation of ART in patients with CM. In Makadzange 2010, at 3 years the all-cause mortality was higher in the early treatment arm (23/28; 82.1%) compared to the delayed treatment arm (12/26; 46.2%). Survival was also lower in the early treatment arm (hazard ratio (HR), 2.34; 95% CI, 1.12-4.89; Adjusted HR, 2.85; 95% CI, 1.1-7.23). In the Zolopa 2009 trial, there was no death in the early treatment arm and 2 deaths in the delayed treatment arm (0.09%). There was one AIDS progression event in the early treatment arm (0.08%) and one in the delayed treatment arm (0.05%). The Zolopa 2009 trial also reported on viral load, CD4-positive-T-lymphocyte count, time to event, adverse events and IRIS, but these data were not disaggregated for CM.

Meta-analysis:

Mortality:

We combined the mortality data for both trials comparing early versus delayed initiation of ART in HIV-infected CM patients. We found that there was no significant difference in the risk of mortality between early and delayed initiation of ART (Pooled relative risk [RR]: 1.40 ; 95% CI: 0.42 to 4.68; P=0.58; I² = 25%) . See Figure 4.

Figure 4.

Forest plot of comparison: 1 Early ART initiation versus delayed ART initiation, outcome: 1.1 Death.

Discussion

Summary of main results

Pooled data from two trials of 89 participants shows that there is no difference in mortality in HIV infected patients with concurrent CM who start ART early (less than four weeks after starting antifungal treatment) versus delayed initiation of ART (4 weeks or more after starting antifungal treatment).

Overall completeness and applicability of evidence

The randomized clinical trial carried out by Makadzange et al (Makadzange 2010) in Zimbabwe was done to show the effects of administering ART before 72 hours after anti-fungal treatment begun as compared to administering it 10 weeks after anti-fungal  treatment was initiated. This was the first occurrence of CM in the patients involved in this study and they  had not had any ART prior to this trial. The treatment for both  groups comprised of oral fluconazole (800mg once daily) and nevirapine- based ART and they followed up for 3 years. The data safety and monitoring board precipitated termination of the study due to the significantly higher mortality rate in the early treatment arm. The reported baseline characteristics of both groups were matched.  The 3-year mortality in the early and late arms was 82.1% versus 46.2% (P=0.005) and median survival in the two arms was 28 and 637 days, respectively (P=0.031). In adjusted analyses, the risk of mortality for the early arm tripled (adjusted HR, 2.85; 95% CI 1.1-7.23). The first 2 weeks of treatment accounted for the majority of the deaths and almost all occurred within 4 weeks. Causes of death were thought to be primarily due to complications of CM.

Although the data interpretation showed that early ART was very strongly associated with a higher risk of mortality, a number of factors need to be considered when interpreting these data (Lawn 2011). ‘Early ART’ was given very early (<3 days) and ‘late ART’ was given very late (>10 weeks). Patients received high-dose oral fluconazole for their cryptococcosis as this is the standard of care in most African countries. It may be linked to a higher risk of IRIS (as opposed to amphotericin), which was potentially a key factor driving mortality in the early arm. Patients were also under routine care of local physicians rather than the study team and did not have protocol-driven monitoring and interventions to reduce intracranial pressure, a very important component of the management of this condition (Meintjes 2010). A major limitation of this study was that there was neither a clinical case definition nor a management plan for cryptococcal IRIS – a likely important cause of raised intracranial pressure and mortality (Müller 2010). Therefore the risk of mortality might have been reduced with the use of amphotericin and proper management of raised intracranial pressure. To minimize this death rate in future study, alternative ART timing strategies, different antifungal medicines, management of raised intracranial pressure and use of adjunctive corticosteroids have to be put into consideration.

The AIDS Clinical Trials Group (ACTG) study A5164 by Zolopa et al (Zolopa 2009) on the other hand was the first randomized controlled trial to be reported and enrolled most of its participants in the USA. Patients involved were in the advanced stage of the disease (median CD4-T-lymphocyte cell count, 29 cells/ml), and had a range of opportunistic infections, excluding TB. These data therefore provided important evidence to support early initiation of ART in patients presenting with acute AIDS-related opportunistic infections or severe bacterial infections with the exclusion of TB. There were, however, an insufficient number of patients with cryptococcal meningitis to inform management of this condition although there was a very strong trend towards lower progression to AIDS or death in those receiving early treatment overall.

The varied populations included in both trials (Puerto Rico, USA, Zimbabwe) would suggest that these findings may be applicable in many settings. However, the limited sample size reduces their generalizability.

Data from the COAT trial (NCT01075152) were not included in our meta-analysis, but seem to suggest that mortality is higher in patients who initiate ART early. This body of evidence will be updated once these data are available.

Quality of the evidence

The Makadzange 2010 trial employed early stopping rules considered acceptable statistical practice (Kim 1987). Use of survival analysis which incorporates the results from all those who completed the trial and who are censored due to loss-to-follow-up or early stopping of the trial, was done to reduce the potential for attrition bias in this trial. In our meta-analysis we present the proportions at the time of stopping the trial. Overall, the quality of this body of evidence is graded as low to very low (Guyatt 2008). Both trials included in our review yielded fewer than 30 events and may thus overestimate the treatment effect. We used the reported data to estimate the optimal information size (OIS) required for a more precise body of evidence. One hundred and four (104) participants are required to have a 80% chance of detecting, as significant at the 5% level, a decrease in mortality from 56% in the early group to 29% in the delayed group (Pocock 1983). The magnitude of effect was inconsistent across both trials, and this resulted in very low evidence in favour of delayed ART initiation. See Summary of findings table 1 for quality of evidence GRADE profiles.

Potential biases in the review process

We conducted comprehensive searches of both journal and conference databases to ensure all relevant published and unpublished trials were identified. We did not limit the searches to a specific language. Given the high-profile nature of the intervention and the complexity of conducting ART initiation trials, it is unlikely that our search strategy failed to detect existing current trial evidence. Potential bias in the conduct of our review was also minimised by having two independent researchers extract data and assess the methodological quality of each study. This detailed process allows for a thorough assessment of trial conduct and an exploration of the possible biases that may be present in each trial. However, we pooled data from only two studies in our meta-analysis. Both trials were slightly different: the Makadzange 2010 trial compared early (initiate ART ⋜ 72 hours after CM diagnosis) versus delayed (initiate ART after 10 weeks of Fluconazole therapy), while the Zolopa 2009 trial compared early (initiate ART ⋜ 48 hours of study) enrolment versus delayed intervention group (initiate ART between week 6 and week 12). Although the Zolopa 2009 trial started patients in the early ART arm within 3 days of study entry, an important difference worth noting is that, study entry was not the time patients started antifungal treatment. Patients in the early arm started ART a median 12 days (inter quartile range: 9-13 days) after starting antifungal treatment for CM. This was different to the Makadzange 2010 trial where patients started ART within 72  hours of starting CM treatment in the early arm. However, given that both trials compared early ART initiation (within 4 weeks of study initiation) we considered this difference to be a minor source of bias.

Agreements and disagreements with other studies or reviews

Administration of ART may depend on the type of infection and the anatomical region it is affecting. IRIS involving the CNS, for example, is generally more severe and associated with higher mortality risk (Bicanic 2008, Peters 1994). A meta-analysis of studies of patients with cryptococcal meningitis starting ART found a pooled incidence of IRIS of 19.5% (95% CI 6.7–44.8) and of these patients 20.8% (5.0–52.7) died (Müller 2010). Thus, approximately 1 in 25 patients starting ART during treatment for cryptococcal meningitis died of immune reconstitution disease. These results are similar to those obtained in our analysis which suggest a possible increase in mortality with early ART initiation, even though this result was not statistically significant. Thus, the possibility that early ART initiation in HIV patients with concurrent cryptococcal meningitis may be associated with adverse overall outcomes cannot be entirely ruled out. Another review including both trials (Makadzange 2010; Zolopa 2009) and a prospective study highlight the conflicting findings concerning the timing of initiation of ART in patients with CM (Grant 2012).

Authors' conclusions

Implications for practice

There is lack of sufficient evidence from the meta-analysis of trials that there is any significant difference in clinical and immunologic outcomes for early initiation ART (less than four weeks after starting antifungal treatment), versus later initiation of ART (four weeks or more after starting antifungal treatment) in HIV-positive patients with concurrent cryptococcal meningitis. Practitioners and policy-makers may consider delaying initiating ART for HIV patients who present to health services and are diagnosed with cryptococcal meningitis because of the possible increase in mortality associated with IRIS. However, evidence for initiating ART in this group of patients remains unclear. For the moment we will recommend that the decision on what time to initiate ART treatment be delayed until there is evidence of a sustained clinical response to antifungal therapy, and informed patient preference.

Implications for research

To the best of our knowledge, there are two published RCTs and two ongoing trials that assess the timing of ART initiation in patients with cryptococcal meningitis. Hopefully, the results from ongoing trials (NCT00976040, NCT01075152) combined with the available trials will provide a larger sample size and adequate follow-up to effectively compare early versus delayed initiation of ART in HIV patients with cryptococcal meningitis. Future research should focus on long-term cohort studies to collect data on the incidence and nature of adverse effects, in early compared to delayed ART initiation. Further research should also involve comparison groups including pediatric and adult patients with HIV and cryptococcal disease.

Acknowledgements

The authors thank The Cochrane HIV/AIDS Group, for conceiving the idea of this review and the help with literature search. A special thank you to George W. Rutherford and Tara Horvath for their assistance and contribution during the process of writing and editing this review. Basile Njei and George Rutherford wrote the final GRADE profiles presented in this review.

Data and analyses

Download statistical data

Comparison 1. Early ART initiation versus delayed ART initiation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death289Risk Ratio (M-H, Random, 95% CI)1.40 [0.42, 4.68]
Analysis 1.1.

Comparison 1 Early ART initiation versus delayed ART initiation, Outcome 1 Death.

Appendices

Appendix 1. Search strategies

1 Search strategy for CLIB (1980 to 2011), Issue 1, 2011  

Footnotes

Number of clinical trials retrieved:  9 records

2 Search strategy for EMBASE (1980 to 2011)  

No.QueryResultsDate
#5 #1 AND #2 AND #3 AND #4 AND [humans]/lim AND [embase]/lim AND [1980-2011]/py3225 Feb 2011
#4 'cryptococcal meningitis'/syn207525 Feb 2011
#3 'human immunodeficiency virus vaccine'/de OR 'human immunodeficiency virus vaccine' OR 'anti human immunedeficiency':ti OR 'anti human immunedeficiency':ab OR 'anti human immunodeficiency':ti OR 'anti human immunodeficiency':ab OR 'anti human immuno-deficiency':ti OR 'anti human immuno-deficiency':ab OR 'anti human immune-deficiency':ti OR 'anti human immune-deficiency':ab OR 'anti acquired immune-deficiency':ti OR 'anti acquired immune-deficiency':ab OR 'anti acquired immunedeficiency':ti OR 'anti acquired immunedeficiency':ab OR 'anti acquired immunodeficiency':ti OR 'anti acquired immunodeficiency':ab OR 'anti acquired immuno-deficiency':ti OR 'anti acquired immuno-deficiency':ab OR 'anti hiv':ti OR 'anti hiv':ab OR antiretrovir*:ti OR antiretrovir*:ab OR 'anti retroviral':ti OR 'anti retroviral':ab OR 'anti retrovirals':ti OR 'anti retrovirals':ab OR 'anti retrovirus':ti OR 'anti retrovirus':ab OR haart:ti OR haart:ab OR 'aids vaccine':ti OR 'aids vaccine':ab OR 'aids vaccines':ti OR 'aids vaccines':ab OR 'anti human immunodeficiency virus agent'/de OR 'anti human immunodeficiency virus agent' OR 'antiretrovirus agent'/de OR 'antiretrovirus agent' OR 'antivirus agent'/de OR 'antivirus agent' OR 'highly active antiretroviral therapy'/de OR 'highly active antiretroviral therapy'50323625 Feb 2011
#2 random*:ti OR random*:ab OR factorial*:ti OR factorial*:ab OR cross?over*:ti OR cross?over*:ab OR crossover*:ti OR crossover*:ab OR placebo*:ti OR placebo*:ab OR (doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab) OR (singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab) OR assign*:ti OR assign*:ab OR allocat*:ti OR allocat*:ab OR volunteer*:ti OR volunteer*:ab OR 'crossover procedure'/exp OR 'crossover procedure'/de OR 'crossover procedure' OR 'double-blind procedure'/exp OR 'double-blind procedure'/de OR 'double-blind procedure' OR 'single-blind procedure'/exp OR 'single-blind procedure'/de OR 'single-blind procedure' OR 'randomized controlled trial'/exp OR 'randomized controlled trial'/de OR 'randomized controlled trial'105568125 Feb 2011
#1 'human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection'/de OR 'human immunodeficiency virus infection' OR 'human immunodeficiency virus'/exp OR 'human immunodeficiency virus'/de OR 'human immunodeficiency virus' OR hiv:ti OR hiv:ab OR 'hiv-1':ti OR 'hiv-1':ab OR 'hiv-2':ti OR 'hiv-2':ab OR 'human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab OR 'human immuno-deficiency virus':ti OR 'human immuno-deficiency virus':ab OR 'human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab OR 'human immune-deficiency virus':ti OR 'human immune-deficiency virus':ab OR 'acquired immune-deficiency syndrome':ti OR 'acquired immune-deficiency syndrome':ab OR 'acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab OR 'acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab OR 'acquired immuno-deficiency syndrome':ti OR 'acquired immuno-deficiency syndrome':ab34179625 Feb 2011

3 Search strategy for PubMed (1980 to 2011)  

SearchMost Recent QueriesTimeResult
#6Search #1 AND #2 AND #3 AND #4 Limits: Publication Date from 1980 to 201108:28:15150
#5Search #1 AND #2 AND #3 AND #408:27:53150
#4Search “Antiretroviral Therapy, Highly Active”[MeSH] OR “Anti-Retroviral Agents”[MeSH] OR “Antiviral Agents”[MeSH:NoExp] OR ((anti) AND (hiv[tw])) OR antiretroviral*[tw] OR ((anti) AND (retroviral*[tw])) OR HAART[tw] OR ((anti) AND (acquired immunodeficiency[tw])) OR ((anti) AND (acquired immunedeficiency[tw])) OR ((anti) AND (acquired immuno-deficiency[tw])) OR ((anti) AND (acquired immune-deficiency[tw])) OR ((anti) AND (acquired immun*) AND (deficiency[tw]))08:27:35112933
#3Search Meningitis, cryptococcal[mh] OR cryptococcal meningitis[tiab] OR Toruloma[tiab] OR Torulomas[tiab] OR Cerebral Cryptococcosis[tiab]08:27:221921
#2Search (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh])08:27:132354755
#1Search HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "sexually transmitted diseases, viral"[MESH:NoExp]08:27:02268875

4 Search strategy for WHO International Clinical Trials Registry Platform (ICTRP)  

Recruitment statusMain ID Public TitleDate of Registration
RecruitingNCT01075152 Trial for the Optimal Timing of HIV Therapy After Cryptococcal Meningitis23/02/2010
RecruitingNCT00976040 Optimal Time to Start Antiretroviral Therapy in HIV-infected Adults With Cryptococcal Meningitis11/09/2009
RecruitingNCT00885703 High-Dose Fluconazole for the Treatment of CM in HIV-infected People20/04/2009
Not recruitingNCT00830856 Early Versus Delayed Antiretroviral Therapy (ART) in the Treatment of Cryptococcal Meningitis in Africa27/01/2009
Not recruitingISRCTN02725351 High dose fluconazole with or without flucytosine in the treatment of human immunodeficiency virus (HIV)-associated cryptococcal meningitiscryptococcal meningitis20/03/2008
Not recruitingISRCTN72024361 Short course interferon-gamma for human immunodeficiency virus (HIV)-associated cryptococcal meningitis23/08/2007
Not recruitingISRCTN68133435 High dose amphotericin B with flucytosine, and amphotericin B plus high dose fluconazole for treatment of cryptococcal meningitis in human immunodeficiency (HIV)-infected patients08/02/2006
Not recruitingNCT00012467 Safety and Antifungal Activity of Recombinant Interferon-Gamma 1b (rIFN-Gamma 1b) Given With Standard Therapy in Patients With Cryptococcal Meningitis09/03/2001
Not recruitingNCT00002305 A Comparison of Fluconazole and Amphotericin B in the Treatment of Cryptococcal Meningitis02/11/1999
Not recruitingNCT00002068 A Multicenter Comparison of Fluconazole (UK-49,858) and Amphotericin B as Treatment for Acute Cryptococcal Meningitis02/11/1999
Not recruitingNCT00002113 A Pilot Study of Fluconazole Plus Flucytosine for the Treatment of AIDS Patients With Acute Cryptococcal Meningitis.02/11/1999
Not recruitingNCT00000639 A Randomized Double Blind Protocol Comparing Amphotericin B With Flucytosine to Amphotericin B Alone Followed by a Comparison of Fluconazole and Itraconazole in the Treatment of Acute Cryptococcal Meningitis02/11/1999
Not recruitingNCT00002306 A Study of Fluconazole in the Treatment of Cryptococcal Meningitis in Patients Who Have Not Had Success With Amphotericin B02/11/1999
Not recruitingNCT00002294 A Study of Fluconazole in the Treatment of Cryptococcal Meningitis in Patients With AIDS02/11/1999
Not recruitingNCT00002077 An Open, Non-Comparative Study of Intravenous and Oral Fluconazole in the Treatment of Acute Cryptococcal Meningitis02/11/1999
Not recruitingNCT00001017 Comparison of Fluconazole and Amphotericin B in the Treatment of Brain Infections in Patients With AIDS02/11/1999
Not recruitingNCT00000776 Dexamethasone in Cryptococcal Meningitis02/11/1999
Not recruitingNCT00000708 Multi-Center Comparison of Fluconazole (UK-49,858) and Amphotericin B as Treatment for Acute Cryptococcal Meningitis02/11/1999
Not recruitingNCT00002074 Multicenter Comparison of Fluconazole (UK-49,858) and Amphotericin B as Maintenance Treatment for the Prevention of Relapse of Cryptococcal Meningitis in Patients With Acquired Immunodeficiency Syndrome02/11/1999
Not recruitingNCT00002075 Multicenter Comparison of Fluconazole (UK-49,858) and Amphotericin B as Treatment for Acute Cryptococcal Meningitis02/11/1999
Not recruitingNCT00002040 Open, Non-Comparative Study of Intravenous and Oral Fluconazole in the Treatment of Acute Cryptococcal Meningitis02/11/1999
Not recruitingNCT00002076 Pilot Study of Oral Fluconazole in the Treatment of Acute Cryptococcal Meningitis02/11/1999
Not recruitingNCT00002019 Safety and Efficacy of Amphotericin B Lipid Complex in the Treatment of Cryptococcal Meningitis in Patients With the Acquired Immunodeficiency Syndrome02/11/1999
Not recruitingNCT00000677 SCH 39304 as Therapy for Acute Cryptococcal Meningitis in HIV-Infected Patients Followed by Maintenance Therapy02/11/1999
Not recruitingNCT00002316 The Safety and Effectiveness of RMP-7 Plus Amphotericin B in Patients With HIV and Cryptococcal Meningitis02/11/1999
     
Footnotes

25 records for 25 trials found for: CRYPTOCOCCAL MENINGITIS AND HIV

Contributions of authors

BN wrote the first draft of the protocol, EJK, and SK provided input for writing the protocol. BN did the literature search. Two co-authors (EJK, and BN) independently assessed trials for inclusion in the review; all the trials that were assessed as excluded were independently reviewed by BN to ensure accuracy of exclusion. The excluded trials were listed along with the reason for exclusion. Selected trials were assessed by EJK, and BN, who independently assessed their quality (study design, randomized treatment allocation, and blinded assessment of outcome). SK resolved any inter-rater differences. BN designed the data extraction form. LM, SK and BN separately extracted data on pre-designed and tested extraction forms; MO, and MJS independently verified all extracted data. BN wrote to authors of various studies to obtain supplementary information including data. BN, LM, SK, EJK, MO, and MJS carried out the statistical analysis and writing up of the review. All co-authors approved the final draft of the review.

Declarations of interest

None known.

Sources of support

Internal sources

  • Cochrane HIV/AIDS Review Group, USA.

External sources

  • No sources of support supplied

Notes

 

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Makadzange 2010

MethodsA prospective, open-label, single-center randomized clinical trial which commenced enrolment in October 2006 in a tertiary referral teaching hospital in Harare, Zimbabwe. The trials were stopped early on in April 2008 by the Data Safety and Monitoring committee (DSMC), and patients were observed through October 2009.
Follow-up was initially every 2 weeks until week 10 during which CSF was sampled. Thereafter, clinical evaluation was performed monthly, CD4-positive-T-lymphocyte cell counts every 3 months and liver function test every 6 months for up to 2 years. Median follow-up time 27 days
Loss to follow-up was 10.7% (3/28) in the early ART group and 11.5% (3/26) in the deferred ART group.
Participants408 HIV-infected adults with cryptococcal meningitis confirmed by Indian ink identification and/or CRAG test
were assessed for eligibility. 315 were excluded and 93 adults met eligibility criteria. Finally, 39 of the eligible patients were excluded because of no consent and 54 patients were enrolled in the study.
Inclusion criteria: HIV-infected+ CM, age ≥ 18 years of age and participants residing within a 50-Km radius of Harare.
Exclusion criteria: History of CM, current ART use, pregnant or breastfeeding,
or had a history of hepatic or renal dysfunction.
Median age was 36.6 years in the EARLY intervention group and 37.5 years in the DELAYED intervention group: 50% males and 50% females in the EARLY intervention group and 54% males and 46%
females in the DELAYED intervention group.
Interventions

Intervention: All participants were started on 800mg/d of Fluconazole at the time of CM diagnosis. After 10 weeks, Fluconazole was reduced to a prophylactic dose of 200mg/d. Cases of treatment failure continued or resumed Fluconazole at 800 mg/d.

EARLY intervention group (initiate ART <= 72 hours after CM diagnosis): Start ART = lamivudine 150mg and Stavudine 30 mg in a fixed-dose combination twice daily and Nevirapine 200mg twice per day, with a 200mg once-daily 2-week lead-in dose. Patients started ART within 72 hours of starting CM treatment.
DELAYED intervention group (initiate ART after 10 weeks of Fluconazole therapy): Start ART = lamivudine 150mg and Stavudine 30 mg in a fixed-dose combination twice daily and Nevirapine 200mg twice per day, with a 200mg once-daily 2-week lead-in dose.

Outcomes

PRIMARY OUTCOME
ALL-CAUSE MORTALITY: Cause of death was ascertained through the hospital records or contacts with next of kin if this occurred at home. Two investigators independently adjudicated and subsequently agreed on the cause of death.
SECONDARY OUTCOME

Serious adverse effects, including: IRIS, TB, severe anaemia, Jaundice, gastroenteritis, pneumonia, cerebrovascular accidents and desquamating rash. deterioration of serum electrolytes, renal function, and bone marrow function,

ADVERSE EVENTS
Was not graded using the Adverse Event Toxicity Scale.

NotesThe trial was funded by the AIDS Care Research in Africa (ACRiA) program and the small grants funding program from the Infectious Disease Society of America.
The trial was approved by the Joint Research Ethics Committee of the University of Zimbabwe College of Health Sciences and Parirenyatwa central hospital, the Medical research council of Zimbabwe, and the Medicines Control Authority of Zimbabwe.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskA computer-generated randomization schedule was used. However, 42% of eligible patients could not be randomized.
Allocation concealment (selection bias)Low riskSealed envelope bearing corresponding number of participant.
Blinding (performance bias and detection bias)
All outcomes
High riskOpen-Label
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskMissing outcome data balanced in number (3) across groups. It is unclear how censoring was done.
Selective reporting (reporting bias)Low riskCompares favourably with protocol on www.ClinicalTrials.gov. Identifier: NCT00830856.
Other biasHigh risk

Stopped early but used survival analysis to overcome effects of attrition.

Discrepancies in reported data.

Zolopa 2009

MethodsA prospective, open-label, multi-centred, randomized, Phase IV clinical trial to study early vs deferred ART in subjects who presented with acute AIDS-related opportunistic infections (OI). The opportunistic infections were a subset of the 1999 CDC's AIDS-defining conditions. Subjects were enrolled between 22 May 2003 and 24 August 2006. The last subject completed the study in August 2007 and data entry was completed by January 2008. Recruitment was conducted at 39 AIDS Clinical trial units in the US and South Africa.
Follow-up was initially every 4 weeks until week 16, thereafter every 8 weeks through week 48.
Loss to follow-up was 4.2% (6/142) in the early ART group and 4.3% (6/141) in the deferred ART group.
Participants283 HIV-infected adults, 35(12%) of them with Cryptococcal meningitis confirmed by Indian ink identification and/or CRAG test were assessed for eligibility.
Inclusion criteria: HIV-infected age >13 years of age and presenting with AIDS-defining OI.
Exclusion criteria: Subjects with or on treatment for TB, ART use with 8 weeks prior to study, more than 31 days of ART within 6 months prior to study entry or more than one ART regimen on which they experienced treatment failure.
Median age was 39 years in the EARLY intervention group and 38 years in the DELAYED intervention group: 85% males and 15% females in the EARLY intervention group and 86% males and 14%
females in the DELAYED intervention group.
Interventions

Intervention:

EARLY intervention group: Initiate ART <= 48 hours after study enrolment. A boosted PI + two nRTIs in 89% of subject and NNRTI-based regimen +two nRTIs in 11% of subjects.

Trial started patients in the early ART arm within 3 days of study entry however, patients in the early arm started ART a median 12 days (Inter quartile range : 9-13 days) after starting antifungal treatment for CM.
DELAYED intervention group: initiate ART between week 6 and week 12 after study enrolment.A boosted PI + two nRTIs in 85% of subject and NNRTI-based regimen +two nRTIs in 15% of subjects.

Outcomes

PRIMARY OUTCOMES
-AIDS progression/Death

-Plasma Viral Load > 50 copies; no progression

-Plasma Viral Load < 50 copies; no progression
SECONDARY OUTCOMES

-CD4-positive-T-lymphocyte cell count at 24 weeks

-CD4-positive-T-lymphocyte cell count at 48 weeks

SAFETY OUTCOMES

-Had at least one ART switch or interruption

-IRIS confirmed

-Hospitalisation and median hospital stay

ADVERSE EVENTS
Laboratory and clinical Adverse Events Grades 2-4 using the Adverse Event Toxicity Scale.

NotesThe trial was supported in part by the AIDS Clinical Trial Group funded by the National Institute of Allergy and Infectious Diseases, AI38858, AI68636 and AI68634. Also supported in part by the General Clinical research Center Units funded by the National Center for Research Resources. All participating sites had local Institutional Review Board approval. All subjects provided written consent.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated randomization using permutation blocks within strata.
Allocation concealment (selection bias)Low riskCentral allocation, participants and the investigators enrolling participants could not foresee assignment.
Blinding (performance bias and detection bias)
All outcomes
High riskOpen-Label
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in number (6) across groups.
Selective reporting (reporting bias)Low riskCompares favourably with protocol on www.ClinicalTrials.gov. Identifier: NCT00055120.
Other biasLow riskThe trial appears to be free of other sources of bias.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Bicanic 2007This prospective observational study did not compare early versus late ART.
Bicanic 2008Sixty-four HIV-seropositive, antiretroviral therapy-naive patients who experienced their first episode of cryptococcal meningitis  were randomized to receive either (1) AmB, 0.7 mg/kg per day, plus flucytosine, 25 mg/kg 4 times per day (group 1; 30 patients); or (2) AmB, 1 mg/kg per day, plus flucytosine, 25 mg/kg 4 times per day (group 2; 34 patients). This trial did not compare early versus late ART.
Bicanic 2010It is an author reply and not a RCT.
Boulware 2010aIt is not a RCT.
Carbonara 2009It is a case report not a RCT.
Chetchotisakd 2004

This was a double-blind, placebo-controlled RCT carried out in HIV-infected patients with CD4-positive-T-lymphocyte counts 

 <100 cells/microL but this study did not compare early versus late ART.

Chimalizeni 2010It is not a RCT.
Chottanapund 2007Retrospective cohort study.
Grant 2010It is an author reply and not a RCT.
Grant 2010aRisk factor analyses for already included trial (Zolopa 2009).
Khawcharoenporn 2007This is a review article not a RCT.
King 2002It was a case report of  paradoxical recurrent meningitis in response to initiation of HAART in a patient receiving maintenance fluconazole for a previous diagnosis of cryptococcal meningitis and not a RCT.
Lawn 2011It was a review article on recently published literature concerning the optimum time to start antiretroviral therapy in patients with HIV-associated opportunistic infections and not a RCT.
Manfredi 1999Case reports and literature review.It was not a RCT.
Manosuthi 2009This randomized trial was conducted in HIV-infected patients receiving three different regimens of fluconazole plus amphotericin B (AmB) for the treatment of cryptococcal meningitis.This trial did not compare early versus late ART .
Martinez 2000It was a prospective study of HIV-1-infected patients who discontinued secondary prophylaxis for cryptococcal meningitis response HAART and It was not a RCT and did not compare early versus late ART.
Müller 2010It was a meta analysis to establish the incidence and lethality of the syndrome in patients with a range of previously diagnosed opportunistic infection; no comparison of early versus late ART.
Pappas 2009It was a randomized, open-label, phase II trial but this study did not compare early versus late initiation of ART in cryptococcal meningitis in HIV patients.
Peters 1994Review article on effects of drugs used in the management of opportunistic infections associated with HIV infection.It was not a RCT.
Portegies 2004 Guidelines for the diagnosis and treatment HIV complications, not a RCT.
Saez 2006It was a case report, not a RCT.
Seddon 2009It was a case series, not a RCT.
Sloan 2008It was a Cochrane systematic review not a RCT.
Vibhagool 2003This study was a  prospective, multicenter, randomized study but did not compare early versus late initiation of ART in cryptococcal meningitis in HIV patients.

Characteristics of ongoing studies [ordered by study ID]

NCT00976040

Trial name or titleOptimal Time to Start Antiretroviral Therapy in HIV-infected Adults With Cryptococcal Meningitis
MethodsPhase IV, Randomized clinical trial to compare early versus standard timing of initiation of antiretroviral therapy (ART) with respect to clearance of Cryptococcus neoformans from cerebrospinal fluid (CSF) among HIV-infected adults with Cryptococcal Meningitis.
Participants

Males and females, 21 years to 80 years of age:

Inclusion Criteria:

-HIV 1 infection confirmed by licensed ELISA kit and/or detectable Viral load. Confirmed Cryptococcal meningitis on the current admission by India ink or CSF cryptococcal antigenART naive at the time of enrolment

-Ability and willingness to give written informed consent to participate in the study

-Able (as assessed by the patient's medical team) to initiate amphotericin B for cryptococcal meningitis -Initiated amphotericin B 72 hours or less prior to assessment for enrolment or not on amphotericin B at the time of assessment for enrolment

-Agrees to obtain outpatient care after discharge within 50 kilometres from Princess Marina Hospital, Scottish Livingstone Hospital and Bamalete Lutheran Hospital.

Exclusion Criteria:

-Recent (within the past 4 weeks) antifungal use

-Pregnant or breastfeeding

-Initiated anti-tubercular therapy 2 weeks or less prior to assessment for enrolment.

-Bacterial meningitis at the time of assessment for enrolment.

-Recent (within the past 1 month) use of the following: systemic cancer chemotherapy, oral or intravenous corticosteroids or other immuno-modulators.

-Judged by study coordinator to be likely to initiate chemotherapy or any other immunomodulatory therapy prior to the 4 week LP.

-Imprisoned.

Interventions

Early antiretroviral therapy: Experimental (Subjects randomized to this arm will initiate antiretroviral therapy within 7 days of enrolment.)

Standard antiretroviral therapy: No Intervention (Subjects randomized to this arm will initiate antiretroviral therapy approximately 4 weeks after enrolment).

In the intervention/experimental arm, triple-drug highly active antiretroviral therapy regimens will be initiated within 7 days of diagnosis of Cryptococcal meningitis.

Outcomes

 Primary Outcome Measures:

-Change in the CSF CFUs between the immediate and standard ART initiation groups.

Secondary Outcome Measures:

-Grade 3 or 4 adverse events
-Clearance of C. neoformans antigen from CSF and blood.
-Change in the number of peripheral blood mononuclear cells responding to C. neoformans.

Starting dateSeptember 2009
Contact information

Contact: Mooketsi Molefi, BSc, MBChB (+267 3170933 ext 205) and Neo Tamuhla, RN, MPH (+267 3170933 ext 206)

Email: mooketsim@botswana-upenn.co.bw and neot@botswana-upenn.co.bw

Notes

The investigators hypothesize that early ART mediates more rapid clearance of C. neoformans from CSF, as manifested by a greater rate of decrease in C. neoformans colony forming units (CFUs) during the first 28 days after initiating antifungal treatment.

Secondary hypotheses are that recovery of pathogen specific cellular immunity directed at C. neoformans, as manifested by increases in the number and function of C. neoformans-specific peripheral blood mononuclear cells is associated with 1) ART and 2) pathogen clearance. In addition, patients randomized to the intervention arm will have more rapid clearance of antigen levels in CSF and serum and will have a lower incidence of grade 3 and 4 Adverse events.

NCT01075152

Trial name or titleTrial for the Optimal Timing of HIV Therapy After Cryptococcal Meningitis (COAT)
MethodsPhase IV, randomized trial to determine after cryptococcal meningitis (CM) whether early initiation of antiretroviral therapy (ART) prior to hospital discharge results in superior survival compared to standard initiation of ART started as an outpatient.
Participants

Male and female patients, 14 years or older.

Inclusion Criteria:

  • HIV-infection, documented by ELISA

  • Antiretroviral medication naive (excluding mother-to-child transmission therapy)

  • Age >14 years

  • Cryptococcal meningitis diagnosed by either culture or CSF cryptococcal antigen (CRAG)

  • Ability and willingness of the participant or legal guardian/representative to give informed consent.

  • Receiving amphotericin-based anti-fungal therapy

Exclusion Criteria:

  • Study entry prior to receipt of <7 days or >11 days of amphotericin therapy

  • History of prior, known cryptococcal meningitis

  • Inability to take enteral medication

  • Receiving chemotherapy or other immunosuppressant medications

  • Cannot or unlikely to attend regular clinic visits

  • Contraindication to immediate or delayed HIV therapy based on serious co-morbidities or co-infections, or laboratory values

  • Pregnancy or breastfeeding

  • Female participants of childbearing potential who are participating in sexual activity that could lead to pregnancy must agree to use two reliable methods of contraception

Interventions

Early HIV Therapy: Experimental [HIV therapy initiated within 48 hours after study entry (at 7-11 days of cryptococcal treatment)]

Standard HIV Therapy: Active Comparator [HIV therapy initiated at >=4 weeks after study entry (at 7-11 days of cryptococcal meningitis treatment), per the usual standard of care].

OutcomesPrimary Outcome Measures: Survival
Starting dateNovember 2010
Contact informationPrincipal Investigator: David R Boulware, MD, MPH
Notes

After 7-11 days of amphotericin B therapy, subjects will be randomized in a 1:1 allocation to:

  • Early initiation of ART (Experimental Group) = ART initiated within 48 hours after study entry, OR

  • Standard initiation of ART (Control Group) = ART at >= 4 weeks after study entry

HIV therapy will be with efavirenz plus nucleoside backbone per national guidelines for first-line therapy.

Ancillary