Slide #1

Antiretroviral Treatment of Adult HIV Infection: 2012 Recommendations of the International Antiviral SocietyUSA Panel
Melanie A. Thompson, MD; Judith A. Aberg, MD; Jennifer F. Hoy, MBBS, FRACP; Amalio Telenti, MD, PhD; Constance Benson, MD; Pedro Cahn, MD, PhD; Joseph J. Eron Jr, MD; Huldrych F. Gnthard, MD; Scott M. Hammer, MD; Peter Reiss, MD, PhD; Douglas D. Richman, MD; Giuliano Rizzardini, MD; David L. Thomas, MD; Donna M. Jacobsen, BS; Paul A. Volberding, MD

Thompson et al, JAMA, 2012.

The International Antiviral SocietyUSA

Slide #2

Available Antiretroviral Agents

Nucleoside RTIs Zidovudine (ZDV)
Didanosine (ddI) Zalcitabine (ddC) Stavudine (d4T) Lamivudine (3TC) Abacavir (ABC) Emtricitabine (FTC)

Nonnucleos(t)ide RTIs
Nevirapine (NVP) Delavirdine (DLV) Efavirenz (EFV) Etravirine (ETR) Tenofovir DF (TDF)

Protease Inhibitors
Saquinavir (SQV) Ritonavir (RTV) Indinavir (IDV) Nelfinavir (NFV) Amprenavir (APV) Lopinavir/r (LPV/r) Atazanavir (ATV) Fosamprenavir (Fos-APV) Tipranavir (TPV) Darunavir (DRV)

Integrase Inhibitors

Boosters Ritonavir (RTV)

Cobicistat* (cobi)

Raltegravir (RAL) Dolutegravir* Elvitegravir*

Fusion Inhibitor
Enfuvirtide (T-20)

* In expanded access or submitted for regulatory approval July 20, 2012

CCR5 Antagonist
Maraviroc (MVC)

Slide #3

Fixed-Dose Combination Antiretrovirals

Abacavir/lamivudine
Elvitegravir/cobicistat/emtricitabine/tenofovir*

Lopinavir/ritonavir
Tenofovir/emtricitabine

Tenofovir/emtricitabine/efavirenz
Tenofovir/emtricitabine/rilpivirine
* In expanded access or submitted for regulatory approval July 20, 2012

Slide #4

Antiretroviral Drugs Available in Generic Forms

Abacavir Didanosine Lamivudine Nevirapine Stavudine Zidovudine

July 20, 2012

Slide #5

IASUSA Antiretroviral Guidelines 1996 2012

Slide #6

2012 IASUSA Antiretroviral Guidelines Authors

Melanie A. Thompson, MD Judith A. Aberg, MD Jennifer F. Hoy, MBBS, FRACP Amalio Telenti, MD, PhD Constance Benson, MD Pedro Cahn, MD, PhD Joseph J. Eron Jr, MD Huldrych F. Gnthard, MD
Scott M. Hammer, MD Peter Reiss, MD, PhD Douglas D. Richman, MD Giuliano Rizzardini, MD David L. Thomas, MD Donna M. Jacobsen, BS Paul A. Volberding, MD

Slide #7

IASUSA Antiretroviral Guidelines

Authored by 15-member, international (6 countries) panel
Members receive no compensation and do not participate in industry promotional activities while on the panel Based upon pathogenesis- and evidence-based individualization of therapy Primarily for clinicians in highly resourced settings; however, principles are universally applicable Reviewed data published or presented 7/10 5/12 Rated on strength of recommendations and quality of evidence Focused on when to start therapy; pre-exposure prophylaxis; what to start; patient monitoring; treatment-experienced patients
Thompson et al, JAMA, 2012.

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Rationale for Issuing Revised Guidelines

Evaluate new data showing all patients may benefit from ART Evaluate new data that ART reduces likelihood of HIV transmission

Consider issues of relevance to persons with hepatic, renal, or cardiovascular comorbidities; opportunistic infections; or at high risk for HIV transmission
Thompson et al, JAMA, 2012.

Slide #9

Methods
Systematic Literature Review of PubMed and EMBASE
Search terms: HIV and antiretroviral and treatment (or prevention or toxicity or monitoring). Filters: English, dates (July 2012-May 2012), humans, adults, clinical trial OR meta-analysis OR guidelines OR editorials OR review OR full text OR free text OR abstracts

Hand searches for newly published reports and scientific abstracts, safety reports ARV manufacturers provided product efficacy or safety data Data not published or presented in a peer-reviewed setting were not considered Thompson et al, JAMA, 2012.

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Methods
Drugs, formulations, combinations considered:
Approved by regulatory agencies (eg, FDA) Available in expanded access program Submitted for regulatory approval (ie, in late development stages)

Thompson et al, JAMA, 2012.

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When to Start

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Risks and Benefits of Earlier Initiation of ART

Benefits
Prevention of progressive immune dysfunction (reduced immune activation) Delayed progression to AIDS and prolonged survival Decreased risk of non-AIDS/HIVrelated morbidity (HIVAN, malignancies,
neurocognitive dysfunction, cardiovascular disease, etc)

Risks
Reduced quality of life Development of drug resistance if adherence is suboptimal Limitation in future choices of ART if drug resistance occurs

Decreased drug resistance Decreased risk for some ARV toxicities Decreased HIV transmission

Uncertain long-term toxicities and duration of effectiveness for some drugs/regimens

Possible transmitted drug resistance

Slide #13

Rationale for Recommending ART for All HIV-Infected Adults

Uncontrolled HIV replication, immune activation and inflammation associated with non-AIDS illnesses
Cardiovascular, hepatic, renal, malignancies ART and high CD4 associated with decreased disease incidence

Patients starting ART when CD4 counts are < 350/L have greater morbidity and mortality than those starting when CD4 counts are < 500/L Increasing evidence of detrimental effects of uncontrolled viremia at CD4 cell counts > 500/L
Thompson et al, JAMA, 2012.

Slide #14

Rationale for Recommending ART for All HIV-Infected Adults

Strength and quality of evidence are highest with
CD4 count < 500 cells/L Pregnancy HBV or HCV coinfection HIV-associated nephropathy Active or high risk for cardiovascular disease Opportunistic infections, including tuberculosis and meningitis Age older than 60 years Primary HIV infection High risk for HIV transmission Thompson et al, JAMA, 2012.

When to Start ART: IASUSA Recommendations 2012

Slide #15

Patient readiness should be considered when deciding to initiate antiretroviral therapy (ART)

ART should be offered regardless of CD4 cell count (increasing strength of the recommendation as CD4 decreases)
CD4 < 500 cells/L (AIa) CD4 > 500 cells/L (BIII) Pregnancy (AIa) Chronic HBV (AIIa) HCV (may delay until after HCV treatment if CD4 > 500) (CIII) Age older than 60 (BIIa) HIV-associated nephropathy (AIIa) Acute phase of primary HIV infection, regardless of symptoms (BIII)

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Initial Regimens in the Treatment-Naive Patient

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Initial Regimen Considerations

Patient readiness to begin lifelong therapy Baseline assessment
Evaluate for HBV or HCV coinfection, diabetes mellitus, hyperlipidemia, cardiovascular disease, smoking, renal disease, other comorbid conditions

Consider drug interactions

Perform resistance testing Assess for pregnancy or risk thereof
Thompson et al, JAMA, 2012.

Slide #18

Recommendations for When to Initiate ART

Patient readiness for treatment should be considered when deciding to initiate ART. Clinicians should engage supportive services as needed to assist with ART education and to address barriers to adherence (AIII) ART is recommended and should be offered regardless of CD4 cell count (AIa-CIII). The strength of the recommendation increases as CD4 cell count decreases and in the presence of certain conditions, with the following grades:
For CD4 cell count of 500/L and below: AIa For CD4 cell count above 500/L: BIII
Thompson et al, JAMA, 2012.

Slide #19

Recommendations for When to Initiate ART (contd)

Ratings for specific conditions are as follows: Pregnancy: AIa Chronic HBV coinfection when HBV treatment is indicated: (AIIa) HCV coinfection: CIII (however, coinfection with CD4 cell count >500/L may delay ART until after completion of HCV treatment) Age older than 60 years: BIIa HlV-associated nephropathy: AIIa

ART is recommended and should be offered to persons during the acute phase of primary HIV infection, regardless of symptoms (BIII) Thompson et al, JAMA, 2012.

Slide #20

Recommendations for When to Initiate ART (contd)

ART should be started as soon as possible, preferably within the first 2 weeks of diagnosis, in patients with opportunistic infections (AIa) The optimal timing for patients with cryptococcal meningitis is less certain, but initiating ART early during cryptococcal treatment may be associated with higher mortality; therefore, ART initiation in these patients should be managed in consultation with experts (BIII)
Thompson et al, JAMA, 2012.

Slide #21

Recommendations for When to Initiate ART (contd)

ART is recommended in all HlV-infected persons with tuberculosis (TB) and should be started within 2 weeks of TB treatment when the CD4 cell count is below 50/L and by 8 to 12 weeks for those with higher CD4 cell counts (Ala). The optimal timing for patients with TB meningitis is less certain, but ART should be started within the first 2 to 8 weeks of diagnosis and managed in consultation with experts (BIII).
Thompson et al, JAMA, 2012.

Slide #22

Choice of Initial Regimen

Tenofovir/emtricitabine (TDF/FTC) OR Abacavir/lamivudine (ABC/3TC) WITH

Third agent (NNRTI, boosted PI, or InSTI):

Efavirenz OR

Atazanavir/r OR
Darunavir/r OR

Raltegravir

Thompson et al, JAMA, 2012.

Slide #23

Recommended Initial Antiretroviral Regimens*

Component
NNRTI plus nRTIs

Recommended Regimens
Efavirenz/tenofovir/emtricitabine (AIa) Efavirenz plus abacavir/lamivudine (AIa) in HLA-B*5701-negative patients with baseline plasma HIV-1 RNA <100,000 copies/mL
Darunavir/r plus tenofovir/emtricitabine (AIa) Atazanavir/r plus tenofovir/emtricitabine (AIa) Atazanavir/r plus abacavir/lamivudine (AIa) in patients with plasma HIV-1 RNA <100,000 copies/mL

PI/r plus nRTIs

InSTI plus nRTIs

Raltegravir plus tenofovir/emtricitabine (AIa)

Thompson et al, JAMA, 2012.

* See comments

Slide #24

Alternative Initial Antiretroviral Regimens*

Component
NNRTI plus nRTIs

Alternative Regimens
Nevirapine plus tenofovir/emtricitabine or abacavir/lamivudine (BIa) Rilpivirine/tenofovir/emtricitabine (or rilpivirine plus abacavir/lamivudine) with baseline plasma HIV-1 RNA < 100,000 copies/mL (BIa)
Darunavir/r plus abacavir/lamivudine (BIII) Lopinavir/r plus tenofovir (BIa) (or abacavir/lamivudine) (BIa) Raltegravir plus abacavir/lamivudine (BIIa) Elvitegravir/cobicistat/tenofovir/emtricitabine** (BIb)
Thompson et al, JAMA, 2012.

PI/r plus nRTIs

InSTI plus nRTIs

* See comment **Submitted for regulatory approval

Slide #25

Initial Antiretroviral Regimens: Comments

Component
NNRTI plus nRTIs

Comments
Severe hepatotoxicity and rash with nevirapine are more common in initial therapy when CD4 cell count is >250/L in women and >400/L in men. Other alternative PIs include fosamprenavir/r and saquinavir/r but indications to use these options for initial treatment are rare. Raltegravir is given twice daily; experience with elvitegravir/cobicistat/tenofovir/emtricitabine is limited to 48-week data.

PI/r plus nRTI

InSTI plus nRTIs

Thompson et al, JAMA, 2012.

Slide #26

CCR5 AntagonistBased and nRTI-Sparing Initial Regimens in Special Circumstances Only

Component
CCR5 antagonist plus nRTIs, (NNRTI-, PI-, and InSTIsparing) PI/r plus InSTI (nRTI-sparing)

Regimens
Maraviroc plus tenofovir/emtricitabine or abacavir/lamivudine (CIII) Darunavir/r plus raltegravir (BIIa) Lopinavir/r plus raltegravir (BIa)

* See comments

Thompson et al, JAMA, 2012.

Slide #27

CCR5 AntagonistBased and nRTI-Sparing Initial Regimens in Special Circumstances Only

Component
CCR5 antagonist plus nRTIs (NNRTI-, PI-, and InSTIsparing)

Comments
Tropism assay to confirm R5 virus should be done before prescribing maraviroc. Maraviroc is not effective in persons who have X4 or dual/mixed X4/R5 virus infection. Few data are available for maraviroc with tenofovir/emtricitabine or abacavir/lamivudine Data emerging for these regimens. Clinical trial evidence needed before formal recommendation can be made.

PI/r plus InSTI (nRTI-sparing)

Thompson et al, JAMA, 2012.

Slide #28

Recommendations for Initial Treatment in the Settings of Specific Conditions

In patients with or at high risk of cardiovascular disease, avoiding use of abacavir, lopinavir/r, or fosamprenavir/r might be considered (BIIa) In patients with reduced renal function, tenofovir should be avoided, or if treatment for HBV coinfection is needed, dosing should be adjusted according to the prescribing information (AIIa) Given the increased risk of fragility fractures, it may be prudent to avoid tenofovir as part of initial therapy in postmenopausal women (BIIa)
Thompson et al, JAMA, 2012.

Slide #29

Recommendations for Initial Treatment in the Settings of Specific Conditions (contd)

The recommended initial ART regimen in the setting of rifampinbased tuberculosis treatment is efavirenz plus 2 nRTls (AIa) The recent recommendation for use of a 3-month, onceweekly regimen of isoniazid with rifapentine for treatment of latent TB infection is not recommended for HlV-infected patients receiving ART (BIII). The ART regimen for HIV- and HBVcoinfected persons should include tenofovir and emtricitabine or lamivudine as the nRTI background (AIIa)
Thompson et al, JAMA, 2012.

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Patient Monitoring

Slide #31

Recommendations for Monitoring

Plasma HIV-1 RNA levels should be monitored at least every 3 months after treatment is initiated or changed for virologic failure to confirm suppression of viremia below 50 copies/mL (AIa). CD4 cell count should be monitored at least every 3 months after initiation of therapy, especially among patients with less than 200/L, to determine the need for primary opportunistic infection prophylaxis (BIII). Once viral load is suppressed for 1 year and CD4 cell count is stable at 350/L or greater, HIV-1 RNA and CD4 cell count can be monitored at intervals of up to 6 months in patients with dependable adherence (CIII). Thompson et al, JAMA, 2012.

Slide #32

Recommendations for Monitoring (contd)

Detectable HIV-1 RNA (>50 copies/mL) during therapy should be confirmed in a subsequent sample between 2 and 4 weeks afterward and prior to making management decisions (BIII) Sustained elevation of HIV-1 RNA between 50 and 200 copies/mL should prompt evaluation of factors leading to failure and consideration of switching of ART (BIII) Baseline genotypic testing for resistance should be performed in all treatment-naive patients (AIIa) and in cases of confirmed virologic failure (AIa)
Thompson et al, JAMA, 2012.

Slide #33

Recommendations for Monitoring (contd)

Therapeutic drug monitoring is not recommended in routine care; however, selected patients (eg, pregnant women, children, and patients with renal or liver impairment) might benefit from this intervention (BIII) Health care practitioners and health systems should initiate strategies to monitor and improve entry into and retention in care and ART adherence and to incorporate and analyze quality-of-care indicators (CIII)

Thompson et al, JAMA, 2012.

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Changing Therapy: When and What

Slide #35

When and What to Change: Principles

Assess possible causes for virologic failure
Nonadherence to drug regimen
Drug interactions

Intercurrent infections
Recent vaccinations

Repeat to exclude measurement error or selfresolving transient viremia

Thompson et al, JAMA, 2012.

Slide #36

When and What to Change: Principles

Regimen intolerance, inconvenience, or toxicity
Single agent substitutions acceptable if virus is suppressed

Monotherapy with boosted PI not recommended

Treatment failure

Treatment goal is virologic suppression to < 50 copies/mL in both initial and multiple failures
Ideally 3, but at least 2, fully active agents
Thompson et al, JAMA, 2012.

Slide #37

Recommendations for Management of TreatmentExperienced Patients In the setting of confirmed virologic failure, changing to a new regimen should occur promptly, with consideration of potential contributory factors to prevent further evolution of drug resistance (AIIa). A new regimen should be constructed using resistance testing (both past and present), treatment history and consideration of tolerability and adherence issues (AIa).
Thompson et al, JAMA, 2012.

Slide #38

Recommendations for Management of TreatmentExperienced Patients (contd) Initial failed regimen should be changed to regimens including a minimum of 2 and ideally 3 fully active drugs (AIa). Management of multidrug resistance is complex and expert advice should be sought (BIII). In virologically suppressed patients, switching single agents for toxicity or prevention of anticipated adverse reactions or drug interactions is generally safe and effective (AIa).
Thompson et al, JAMA, 2012.

Slide #39

Recommendations for Management of TreatmentExperienced Patients (contd) Intensification of or switching therapy has not been successful in improving suboptimal CD4 cell count responses in the setting of durable virologic suppression and is not recommended (AIa). Treatment interruptions (outside of clinical trial) should be avoided because of increased risk of death, AIDS, and serious non-AIDS morbidity associated with untreated HIV infection (AIa).
Thompson et al, JAMA, 2012.

Slide #40

Recommendations for Management of TreatmentExperienced Patients (contd) PI/r monotherapy is associated with an increased risk of virologic failure and is not recommended when other options are available (AIa).

Thompson et al, JAMA, 2012.

Slide #41

Conclusions

Slide #42

Conclusions I
Recommendation to begin therapy earlier in asymptomatic persons is informed by
Increased evidence of the harmful effects of uncontrolled viremia and its associated immune activation and inflammation, even at higher CD4 cell counts Evidence that all HIV-infected adults may benefit from ART Data showing ART reduces likelihood of transmission Thompson et al, JAMA, 2012.

Slide #43

Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012 ART is recommended and should be offered regardless of CD4 cell count (A1a-CIII depending on CD4 cell count and existing conditions). ART is recommended and should be offered to persons during the acute phase of primary HIV infection, regardless of symptoms (BIII).

Thompson et al, JAMA, 2012.

Slide #44

Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012 (contd)

ART should be started as soon as possible, preferably within the first 2 weeks of diagnosis, in patients with opportunistic infections (other than cryptococcal and tuberculous meningitis),with attention to drug interactions and the potential for immune reconstitution inflammatory syndrome (IRIS) (AIa). The optimal timing of ART initiation in patients with cryptococcal meningitis is less certain, but initiating ART early during cryptococcal treatment may be associated with higher mortality; therefore, ART initiation in patients with cryptococcal meningitis should be managed in consultation with experts (BIII). Thompson et al, JAMA, 2012.

Slide #45

Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012 (contd)

ART is recommended in all HlV-infected persons with TB and should be started within weeks of TB treatment when CD4 cell count is below 50/L and by 8 to 12 weeks for those with higher CD4 cell counts (AIa).The optimal timing for patients with TB meningitis is less certain, but ART should be started within the first 2 to 8 weeks of TB treatment and managed in consultation with experts (BIII). Abacavir/lamivudine (in patients with HIV-1 RNA levels < 100,000 copies/mL) is now a recommended rather than alternative dual nRTI component of initial ART (AIa).
Thompson et al, JAMA, 2012.

Slide #46

Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012 (contd)

Rilpivirine has been added as an alternative NNRTI component of the initial regimen (BIa). Coformulated elvitegravir/cobicistat/tenofovir/emtricitabine has been added as an initial regimen component, pending regulatory approval (BIb). Elvitegravir is an investigational InSTI and cobicistat is an investigational pharmocokinetic booster. Given increased risk of fragility fractures in postmenopausal women, it may be prudent to consider avoiding tenofovir as part of initial therapy in this group (BIIa).
Thompson et al, JAMA, 2012.

Slide #47

Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012 (contd)

The recommended initial ART regimen in the setting of rifampin-based TB therapy is efavirenz plus 2 nRTIs (AIa). The recent recommendation for use of a 3-month, onceweekly regimen of isoniazid with rifapentine for treatment of latent TB infection is not recommended for HlV-infected patients receiving ART (BIII). Sustained elevation of plasma HIV-1 RNA between 50 and 200 copies/mL should prompt evaluation of factors leading to failure and consideration for switching of ART (BIII). Thompson et al, JAMA, 2012.

Slide #48

Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012 (contd)

Health care practitioners and health systems should initiate strategies to monitor and improve entry into and retention in care and ART adherence and to incorporate and analyze quality-of-care indicators (CIII). Management of multidrug resistance is complex and expert advice should be sought (BII).

Thompson et al, JAMA, 2012.

Slide #49

Earlier ART Associated with Decreased Mortality and Disease Progression: Observational Studies
Study
NA-ACCORD NA-ACCORD When to Start Consortium HIV-CAUSAL CASCADE COHERE

Published
NEJM, 2009 NEJM, 2009 Lancet, 2009 Ann Int Med, 2011 Arch Int Med, 2011 Plos Med, 2012

N
8,362 9,155 24,444

Endpoint
Death Death AIDS or Death AIDS or Death

Relative Hazard
1.69 CD4 <350 vs 350-500 1.94 CD4 <500 vs > 500 1.28 CD4 251-350 vs 351-400 1.38 CD4 <350 vs <500 0.51 (HR)* CD4 350-499 vs deferred 0.74 (HR)* CD4 350-<500 on ART 0.96 (HR)* CD4 > 500 on ART

P or 95% CI
< 0.001 < 0.001

9,455 75,336

Death AIDS or Death

0.33-0.80 0.58-0.80 0.92-0.99

Slide #50

CASCADE Seroconvertor Cohort

Compared with deferred ART in any given month, starting ART was associated with slowed disease progression in all CD4 strata except 500-799 cells/L
$$$Add reference$$$

Slide #51

HPTN 052
1,750 heterosexual serodiscordant couples in resourceconstrained countries randomized to receive ART early (CD4 350-550 cells/L) or defer until CD4 < 250 cells/L
(Cohen M, et al. NEJM 2011)

Event Rates

Early ART

Deferred ART

HR

P-value

Transmission Rate per 100 pt-years (95% CI) Clinical Event Rate per 100 pt-years (95% CI)

0.3 (0.1-0.6)

2.2 (1.6-3.1)

0.11 (0.04-0.32)

< 0.001

2.4 (1.7-3.3)

4.0 (3.5-5.0)

0.59 (0.40-0.88)

<0.001

Cohen et al, NEJM, 2011

Slide #52

Effect of ART Timing on TB Death (CAMELIA) or Death/AIDS Progression (STRIDE, SAPIT)

19% p=0.45
Earlier: 2-4 weeks after TB treatment started Later: 8-12 weeks after TB treatment started

34% p=0.004

11% p=0.73

Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011

Slide #53

Significant Reduction in Death/AIDS Among Those with TB and CD4 < 50 Cells/L
42% p=0.02 68% p=0.06
Earlier: 2-4 wks after TB treatment started Later: 8-12 wks after TB treatment started

34% p=0.004

Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011

Slide #54

Greater Reduction in Mortality at Lower CD4

P = 0.004

P = 0.45
P = 0.73

Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011

Cryptococcal Meningitis and Antiretroviral Therapy

Slide #55

Randomized clinical trial in Zimbabwe; ART started within 72 hours vs. 8 weeks after initiation of fluconazole alone for treatment of CM (Makadzange C, et al.
Clin Infect Dis 2010)

Trial stopped by the DSMB due to increased HR for death (HR 2.85) in the early ART arm

Randomized clinical trial in Uganda, South Africa (COATS) in patients with CM

After 7-11 days of treatment with amphotericin B + fluconazole, patients were randomized to start ART within 48 hours or > 4 weeks Trial stopped by the DSMB due to increased mortality in the early ART arm

When to Start ART During Acute Opportunistic Infections: IASUSA Recommendations 2012

Slide #56

Start ART as soon as possible, preferably within the first two weeks (AIa) except for TB and cryptococcal meningitis as indicated below:
Patients with cryptococcal meningitis should be managed in consultation with experts (BIII) Patients with TB should start TB treatment first; start ART as soon as possible but within the first 2 weeks for those with CD4 < 50 cells/L Within the first 2-8 weeks of TB treatment for those with TB meningitis Within the first 8-12 weeks of TB treatment for others