The comprehensive 40-page document includes a detailed review of the most important routine monitoring. It is an essential reference for understanding the current recommended minimum standard of care.

These guidelines include suggestions for audited targets and cover each stage of the treatment pathway from initial diagnosis, through to naïve and experienced management, and includes the case of transferred care.

It is also important for highlighting simple and inexpensive aspects of care that are important but if overlooked have the potential to greatly impact on patient quality of life. These include full patient history, psychological assessment (including depression, anxiety and social support), sexual history (including sexual health), support for evaluating adherence, baseline evaluations (including physical examination, waist circumference, blood pressure and BMI). Mental health has a separate consideration.

Recommendations for CD4 and viral load monitoring are similar to earlier guidelines. In naïve patients, as long as CD4 count remains 100 cells higher than the threshold for starting treatment (currently this would be 450), CD4 monitoring should be every 4-6 months, and 3-4 monthly if it falls below this. CD4 count should still be monitored four weeks after starting therapy (with viral load). In people who maintain an undetectable viral load for more than one year and whose CD4 count is greater than 200, CD4 monitoring can be reduced to six-monthly.

Viral load should still be a factor when deciding to initiate HAART, needing at least two results for patients in chronic infection to establish a reliable set point, six monthly thereafter and repeated within one month prior to treatment. Short term efficacy needs to be confirmed by a drop of at least I log, four weeks after starting treatment, and further tests at 3 and 6 months. Undetectable (<40 or <50 copies/mL) should be achieved by 4-6 months. Subsequent monitoring should be 3-4 monthly, and six-monthly viral load can be considered in a strictly adherent patients on stable treatment. Viral rebound to >50 copies/mL needs to be conformed with a new sample.

The cut-off for switching treatment is only briefly mentioned but blips are described as transient increases to between 50 and 1000 copies/mL (subsequent test being < 50 copies/mL) and multiple blips a signal to review drug potency, adherence, tolerability, resistance and potential modifications to the combination.

Resistance testing is still strongly recommended for all newly diagnosed patients and again prior to starting treatment if reinfection is possible, or in patients without results from first diagnosis, at week four of treatment if viral suppression is less than 1 log copies/mL, in all patients with confirmed viraemia (while on the failing combination) recognising that specialised labs are able to work with samples where viral load is ‘just over’ 50 copies/mL.

The guidelines also address laboratory monitoring for renal, hepatic, cardiovascular, bone and biomarkers, other infections including sexual health and for specific patient groups (women, older patients, injecting drug users and late presenters.

References and links:

British HIV Association guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals 2011

BHIVA site link:

http://www.bhiva.org/Monitoring.aspx

HIV Medicine, January 2012 Volume 13, Issue 1 Pages 1-88.

http://onlinelibrary.wiley.com/doi/10.1111/hiv.2011.13.issue-1/issuetoc

The scope of this document includes guidance on the initiation of ART in those previously naïve to therapy, support of patients on treatment, management of patients experiencing virological failure and recommendations in specific patient populations where other factors need to be taken into consideration.

The Treatment Guidelines Writing Group is grateful for all comments, which will be reviewed before publication.

Comments can be made online at the same URL for the draft document:

http://www.bhiva.org/treatmentguidelinesconsultation.aspx

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These guidelines have been produced based using a new methodology and grading system compared to earlier documents, and are clearly the result of considerable additional work.

The evidence base is published in a separate 270 page appendix.

Of note, some of the recommendations in the current draft include differences between the BHIVA writing committee and current prescribing by the London consortium.

Readers have until 5 March to comment.

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of HIV-infected pregnant women.

The scope includes guidance on the use of ART therapy both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration such as co infection with other agents.

Comments can be made online at the same URL for the draft document:

http://www.bhiva.org/PregnancyGuidelinesConsultation.aspx

The London HIV Consortium, the pan-London commissioning group for HIV services, has just outlined the results of the tender process for purchasing HIV drugs for the next two years. This is part of an ongoing process to manage the HIV budget within government-imposed restrictions on NHS budgets. Over two years the group is faced with having to make savings of approximately £10 million to mange the same service on a budget that has not increased in line with inflation.

This will change the way that some HIV drugs will be prescribed in London. Although there are circumstances where the choice of when to use each drug has changed, all drugs will still be available for different situations.

Initially the changes mostly affect the choice of treatment for people who are starting treatment. Most people who are currently on stable treatment will not be asked to change treatment. However, some people on stable treatment will be asked to switch one or more of their current drugs.

The main changes are:

• More people starting treatment will start with a combination of two pills rather than one pill once a day.
• Some people on current treatment will be asked to change to a similar alternative treatment.

This policy for broadly influencing prescription practice has been part of London drug commissioning for many years.

The details of these changes are explained below.

Cost is the principal reason behind the changes. Widespread cuts across the NHS include nearly all services. HIV is no different to any other service in this respect. Prescribing the most cost effective treatment first will help protect other aspects of HIV services. HIV treatment is also very individual. Treatment will continue to be individualised for each person’s circumstances.

Outline of 2011 process

This year the Consortium changed the process of purchasing drugs. This required drug manufacturing companies to tender bids for the costs of their drugs for a range of clinical settings, for example for first-line therapy or for first treatment failure etc. This process has taken several months. It has involved input from doctors from the leading HIV hospitals, pharmacists and community advocates.

The tender included the option for a sliding scale of costs if larger quantities are used.

The principles for this process are important:

• No drug will be excluded from being prescribed. The range of individual patient responses makes it likely that in some circumstances there will be a clinical need for some people to use different combinations to those recommended.
• The guidelines for use of treatment are supported by evidence. The decisions were not determined just by the cost of a drug. The decision on accepting a drug tender are dependent on them being effective and reducing the risk of side effects. The cheapest drugs were not selected if they were not as effective or had greater side effects. This process will not result in widespread use of less effective drugs simply because they are priced cheaply. However, where two options are broadly similar but have a significant difference in costs, the less expensive drug will be preferred.
• These measures are being taken due to financial constraints being imposed throughout the NHS. If HIV care does not respond by providing the cost-effective treatments, then cuts are more likely to be made in other HIV services: reduced clinic time, fewer doctors and nurses, shorter appointments and reduced monitoring.

All manufacturers had the opportunity to modify aspects of their bids to standardise them with other aspects of the tender process, especially in relation to the staggered price related to the volume of drugs purchased.

These budget estimates are dependent on reaching projected target volumes for each drug, including maintaining current drugs levels for some existing drugs. In order to reach or maintain these targets over the year, every London clinic will be working to the same guidelines. Although a clinic can prescribed outside these guidelines the drug costs for those patients will not be reimbursed by the London HIV Consortium.

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HIV care is faced with the challenge of being managed and maintained under the financial constraints being imposed on the NHS. This has to be done without jeopardising patient care and these guidelines have the potential to improve patient care in many cases.

An audit will track the outcomes from key treatment changes, initially at three-monthly intervals, to confirm that safety and efficacy is maintained.

These recommendations broadly fall within the BHIVA guidelines (though these have not been significantly revised since 2008), which include the importance of cost effectiveness when clinical data support several therapeutic choices.

HIV care remains one of the most cost-effective medical interventions. These proposed changes minimise disruptions to patient care, maintain access to high quality drugs and retain flexibility for individualised care.

Although this tender is for two years the clinical guidelines will be reviewed and changed if new research raises concerns about the clinical use of any of the preferred drugs.

What this means in practice

The recommendations for people starting treatment and people already on treatment and are summarised below.

1. Treatment-naïve patients

Preferred option:

a) Efavirenz or nevirapine plus coformulated abacavir/3TC (Kivexa)

When there are clinical reasons not to use any of these drugs, alternatives can of course be used. This includes drug resistance, concern for side effects, shift work, pregnancy, high viral load (over 100,000 for abacavir) or high risk of heart disease (a greater than 10% risk over ten years, again for abacavir). If abacavir/3TC is not appropriate tenofovir/FTC is recommended.

Alternatives:

a) Atazanavir/r is recommended as the first choice if efavirenz or nevirapine are not appropriate.

b) Tenofovir/FTC is recommended when abacavir/3TC is not appropriate.

c) Other drugs can be used when there is a clinical need. For example, alternative protease inhibitors can be used whenever these are clinically more appropriate.

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This main change for people starting treatment is that there will be more people using two pills a day rather than one. First-line treatment will still use once-daily combinations and number of daily doses is probably more important than daily pill count. All the recommended combinations are already widely used.

In practice this should not be a significant problem for most people. Most people prefer one drug to two, but there are few studies that show it makes a difference to adherence or to clinical results. While the ease of use of single-pill formulations are popular, there are little data suggesting that one vs two pills daily has a poorer clinical outcome.

When there are clinical reasons to use alternatives, these will still be used. Common reasons not to use abacavir/3TC includes a higher risk of heart disease and a viral load >100,000 copies/mL when starting treatment (based on ACTG 5202). For a few people this might also include higher lipids as tenofovir/FTC has a better lipid profile than abacavir/3TC.

Atazanavir/r is already a widely used, once-daily protease inhibitor that is generally easy to tolerate and easy to modify in case of side effects. This has the potential to improve combinations, for example for people currently taking twice-daily protease inhibitors. Switching to alternatives, including back to the original treatment is possible at all stages if this is needed.

The commissioners already influence drug prescribing. Currently there are financial incentives for clinics to start at least 85% of new patients on NNRTI-based combinations using CQUINs (DoH Commissioning for Quality and Innovations). For 2011/12 clinics that do not broadly follow the new guidelines, threatening to derail the pan-London approach, will having their drug budget witheld entirely.

2. People currently on stable treatment

a) Some people using protease inhibitor-based treatment that does not include atazanavir will be recommended to switch to using atazanavir-based combinations unless there is a clinical reason to stay on their current treatment. These reasons could include previous side effects and drug resistance. Only the protease component of the combination is being recommended to switch.

b) People currently on NNRTI-based stable treatment are not being asked to switch. People currently using Atripla will not be asked to change from Truvada (tenofovir/FTC) to Kivexa (abacavir/3TC), although they do have this option. This decision may be reviewed in the future, but is unlikely to change in the short-term. This is is dependent on clinics across London following the general guidelines for new and existing patients.

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The protease inhibitor switch may improve treatment for many people as this may include reduced doses and lower pill counts with some changes.

The staggered approach to switching people who are stable on their current treatment is dependent on clinics across London following the general guidelines for new and existing patients.

These guidelines might also prompt a review to switch patients on older treatments that are not recognised as first choice options in BHIVA guidelines.

3. Use of raltegravir

Raltegravir will still be used predominantly by people with documented triple-class resistance. It can also be used in a limited number of other situations where there is a clinical need. This includes cases where a rapid reduction of viral load is important (for example HIV diagnosis in late pregnancy) or to avoid drug interactions (for example with chemotherapy). The higher cost of raltegravir compared to other first-line and second-line drugs is the reason behind this more restricted access.

Raltegravir can be prescribed by any doctor outside of these guidelines but the cost of the treatment will have to be paid by the hospital rather than by the London Consortium.

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Raltegravir was initially developed as a treatment for people with drug resistance. It was also priced higher as a life-saving drug rather than a treatment for standard therapy. Although the cost for raltegravir has come down it is still more expensive that alternative switching options. It is disappointing that the cost of raltegravir currently limits prescribing at any treatment stage as the potential advantages of raltegravir over protease inhibitors include reduced side effects such as less impact on lipids (cholesterol and triglycerides). The disadvantages of raltegravir include fewer long-term data as it is a newer drug, needing to use twice-daily dosing, and that previous drug resistance limits the ability to switch easily from a protease inhibitor to raltegravir. Several studies have shown an increased risk of treatment failure compared to staying on a protease inhibitor.

Additional background

HIV-positive people will be able to discuss these proposals with their doctor. As with all treatment decisions, discussing options with the medical team is always recommended.

For many years, antiretroviral drugs have been bought on a pan-London basis by the London HIV Consortium as part of a way to deliver equity of care for HIV-positive people in all boroughs, independently of which London clinic they attend. Each year this group negotiates the price of each drug with each company.

While the process of drug pricing has a low profile amongst most people who use treatment, it is very complicated. The cost of a drug rarely is the same as its list price. This has led to many improvements in HIV care including greater prescribing consistency and access and use of the newest drugs. This group is as focussed on the quality of care as it is on costs, and it has developed a range of services that have improved patient care.

For example, the same London HIV Consortium are responsible for establishing the New-Fill service to correct facial fat loss in NHS clinics in London. It has also helped maintain routine services by saving costs with other initiatives such as expanding home delivery of drugs (this saves VAT costs that are otherwise charged on hospital prescribed medicines).

By ring-fencing high cost drugs for people with most extensive drug resistance, this ensured equity of access to the most extensive treatment for people whose virus was most difficult to treat.

Simon Collins is a member of the London HIV Consortium Drug and Treatment Sub-Committee.

HIV i-Base receiving no funding from the London HIV Commissioners.

References and links:

The London Consortium Drug Group included lead clinicians from London clinics, HIV-specialist pharmacists, community advocates, HIV-positive people and health commissioners. Document from the group will be posted online.
http://www.londonspecialisedcommissioning.nhs.uk/

A slide set summary of the recommendations in PDF and the Powerpoint files are available from the i-Base website.
http://www.i-Base.info/changes-to-hiv-drug-prescribing-in-london

The new WHO 2010 paediatric guidelines – Antiretroviral Therapy for HIV Infection in Infants and Children: Towards Universal Access – also summarised on their website in a preliminary version for programme planning in June, were released at IAS 2010.

Lynne Mofenson provided an excellent summary of the new guidelines at the paediatric meeting and Shaffiq Essajee in the Early Infant Diagnostics (EID) session at IAS. [1,2] We will review developments in diagnostics including EID in the next issue of HTB.

When to start

Universal treatment is recommended for all infants and young children under two years irrespective of CD4 or clinical indication. The recommendation is strong for less than 12 months and conditional for 12-24 months.

Data to guide when to start for children one to five years old are scant and this is reflected in differences in recommendations between guidelines (see statement from PENTA in the comment below). After five years of age, guidance is similar to that for adults (see Table 1). Table 2 shows a comparison between the 2006 and 2010 WHO guidelines.

*CD4 percentage/absolute CD4 count mm3

Adapted from WHO 2010 revision. Essajee S.

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PENTA have published a letter in support of the new guidance for resource limited settings and are continuing to recommend PENTA guidance ie universal treatment for infants less than 12 months and immunological and clinical criteria for those above for treating children in Europe. In the letter they write:

“Both PENTA 2009 and WHO 2010 guidelines considered the same body of evidence, and several experts took part in the drafting of both sets of recommendations. The universal treatment of infants is based on evidence from the CHER study, children over five are treated at adult thresholds in both guidelines, based on comparisons between the HPPMCS child cohort and CASCADE adult seroconverter cohort. The recommendations for children aged between 2 and 5 are based on cohort data, largely from the HPPMCS study.

The new recommendations in the WHO guidance for children between age one and five are based on programmatic considerations, in particular the ability to closely monitor a child clinically and by repeat CD4 count measurement if they are not started on ART. Such monitoring is available in Europe, and in many settings outside Europe. It is also noted that the evidence basis for these recommendations is weak or very weak, and that studies expected to publish results soon may shed more light on the subject. We endorse WHO’s recommendation to treat early where the ability to provide monitoring is limited, as well as the call for more research to provide RCT evidence for treatment initiation thresholds after infancy. We continue to recommend PENTA 2009 guidance as appropriate for European and other settings with the facility to monitor closely children in whom treatment is deferred.”

http://www.pentatrials.org/PENTA%20letter%20re%20WHO%20jul%202010.pdf

What to start with

Recommended regimens are:

• For children less than two not exposed to maternal or infant nevirapine or whose exposure status is unknown: nevirapine plus two NRTIs.
• For children exposed to maternal or infant nevirapine or other NNRTIs used for maternal treatment or PMTCT: lopinavir/ritonavir plus two NNRTIs (with the caveat that nevirapine is better than nothing).
• For children over two but under three: nevirapine plus two NRTIs.
• All others (irrespective of nevirapine exposure): nevirapine or efavirenz (efavirenz preferred for TB treatment)
• Under three and needs TB treatment: nevirapine plus two NRTIs or abacavir plus lamivudine plus zidovudine/stavudine.
• • Adolescents over 12 with hepatitis B: tenofovir plus lamivudine/emitricitabine plus efavirenz/nevirapine (can take FDC of lamivudine/emitricitabine plus efavirenz if this is available).
• Adolescents with hepatitis C: preferred regimen is efavirenz plus two NRTIs.

The guidelines also recommend a preferential order of NRTIs (zidovudine/lamivudine > abacavir/lamivudine > stavudine/lamivudine).

They recommend that any child with active TB begin TB treatment immediately and start ART in the first eight weeks of TB treatment.

For children already on ART who develop TB, they recommend that ART regimens may need to be adjusted to decrease the potential for toxicities and interactions: if on nevirapine substitute for efavirenz if over three years; if under three ensure nevirapine is at high dose (2 mg/m2) and if on lopinavir/ritonavir consider adding ritonavir to a 1:1 ratio lopinavir/ritonavir to achieve the full therapeutic dose of ritonavir.

The guidelines recommend solid in preference to liquid formulations, use of heat stable FDCs or co-packaged formulations wherever possible and dosing in accordance with WHO weight band tables.

When to switch

Switching to second line treatment is recommended when clinical, immunological or virological failures occur.

• Clinical failure is defined as the appearance (or reappearance) of WHO clinical stage 3 or 4 events at least 24 weeks on ART and child is adherent.
• Immunological failure is defined as returning to age related thresholds in a treatment adherent child: CD4 count of <200 cells/mm3 or CD4 percentage <10% for a child over two and less than five years of age; CD4 count of <100 cells/mm3 for a child of five years or more.
• Virological failure is defined as a persistent viral load above 5000 copies/mL after at least 24 weeks on ART for a treatment adherent child.

What to switch to

Choice of second line ART is dependent on the first line regimen received:

• After failure on an NNRTI: boosted PI plus 2NRTIs. Lopinavir/r is preferred.
• After failure on zidovudine or stavudine plus lamivudine: abacavir plus lamivudine is the preferred NRTI backbone, abacavir plus didanosine is an alternative.
• After failure on abacavir plus lamivudine, zidovudine plus lamivudine is the preferred NRTI backbone; zidovudine plus didanosine is an alternative.

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These guidelines represent a liberalisation of criteria and if they are followed should ensure that many more children are identified and treated.

They are available on the WHO website. [3]

Annexe E has updated weightband dosing tables and formulations that are needed. We also look at paediatric formulations in the TAG/i-Base Pipeline Report. [4]

References:

1. Mofenson L. What’s new in WHO Pediatric Treatment Guidelines? 2nd International Workshop on HIV Pediatrics. July 2010, Vienna, Austria.
   http://regist2.virology-education.com/2ndHIVPed/docs/I_04Mofenson.pdf
2. Essajee S. Scaling up early infant diagnosis of HIV as the bridge between prevention, care and treatment: successes, challenges and potential solutions. Special session SUSS03.
   http://pag.aids2010.org/session.aspx?s=150
3. World Health Organisation. Antiretroviral therapy for HIV infection in infants and children : Recommendations for a public health approach (2010 revision)
   http://www.who.int/hiv/pub/paediatric/infants2010/en/index.html
4. Clayden P. Paediatric antiretroviral pipeline. TAG 2010 Pipeline Report. July 2010.
   http://i-base.info/htb/13436

The revised 2009 WHO guidelines have four major changes since the 2006 edition:

• Routine CD4 counts
• Earlier ART initiation – CD4 threshold of 350 cells/mm3 from 200 cells/mm3
• Changing d4T to tenofovir in first-line regimens
• Increased number of sequential lines of treatment

In an oral session, Rochelle Walensky from Harvard presented findings from a study using a mathematical model simulated to project the clinical and economic outcomes from implementing each of these changes and combinations of these changes.

This study was designed to assist policy makers with their prioritisation process in recognition that implementing all of the guideline changes immediately poses major challenges in most resource limited settings.

The study used input data from a South African cohort with a mean age 32 years and a mean CD4 count of 375 cells/mm3 (ie healthier patients with the potential to benefit from starting earlier). Other input parameters included 24-week ART suppression rates of 75% and 78% rate of suppression at 24-weeks for first and second line ART respectively; annual costs of $36 and $135 for d4T and tenofovir respectively and 1.7-2.6% and 0.4-1.6% incidence of d4T and tenofovir related toxicity were also used.

The investigators ranked, in terms of survival and cost effectiveness, all 13 possible combinations of: (1) ART initiation at CD4 <200 cells/mL or CD4 <350 cells/mm3; (2) Replacing d4T with tenofovir; and (3) Number of available treatment regimens (1 or 2).

They examined 5-year survival, projected life expectancy and incremental cost effectiveness of different treatment scenarios. They used the WHO definition of less than 1x per capita GDP as the threshold for “very cost effective”. For South Africa this is <$5,400 per year of life saved.

The baseline assumption was that patients received a single, d4T-based ART regimen, initiated at WHO Stage III/IV.

Dr Walensky reported that the projected baseline survival was 99 months, with a 65% 5-year survival rate. Switching from d4T to tenofovir gave a modest improvement, with a 110-month life expectancy and 67% 5-year survival. Adding ART at <200 cells/mm3 to baseline gave a 116 month life expectancy and 80% 5-year survival. Adding a second line regimen increased life expectancy to 121 months but added little to 5-year survival (66%) compared to baseline. Adding ART started at <350 cells/mm3 increased life expectancy to 124 months and 5-year survival to 87%.

Stepwise additions of switching to tenofovir or adding a second-line regimen to a one line d4T-containing regimen initiated at 350cells/mm3, gave increased life expectancy of 140 and 178 months and 91% five year survival (for both changes) respectively.

Switching to tenofovir from d4T in addition to initiating at 350 cells/mm3 and adding a second-line, ie following the complete WHO revisions, increased life expectancy to 192 months with 91% 5-year survival.

Dr Walensky summarised the above results noting that the incremental life expectancy gains are maximised with the following stepwise programmatic additions: first – the expansion of ART eligibility to CD4 <350 cells/mm3 one-line (124 months); followed by the addition of second line therapy (178 months); finally followed by the replacement of d4T with and tenofovir (192 months).

When examining the incremental cost-effectiveness of alternative programmes, three were found to be economically effective: d4T 350 cells/mm3/one-line (cost-effectiveness ratio $610/year of life saved [YLS]), tenofovir/< 350 cells/mm3/one-line ($1,410/YLS), and tenofovir/<350 cells/mm3/two-lines ($2,230/YLS). The investigators noted that these results persisted despite plausible variation in efficacy and cost assumptions.

The results of this study are extremely sensitive to the price of tenofovir. A sensitivity analysis revealed a decrease in the price of tenofovir from $135 to $51 per person year would make tenofovir more effective and less costly than d4T.

Dr Walensky suggested that the limitations to this study were that it only shows results for people initiating ART and did not address people in ongoing care. Also that while the analysis looks at value for money it does not project the implications of each component of the WHO recommendations on programme budgets.

To the question “What to do first” she concluded that the decision is dependent on a country’s current policy and capacity. In countries without laboratory capacity, CD4 monitoring and ART at <350 cells/mm3 is the most crucial priority to start with. Where this is already available, replacing d4T with tenofovir are both cost effective and give survival benefits. The addition of second-line ART offers greater survival benefit but with substantial increases in total costs.

Reference:

Walensky R et al. Scaling up WHO recommendations for HIV therapy in resource-limited settings: what to do first? Oral abstract WEAE0205.

The South African Antiretroviral Treatment guidelines have finally been updated. [1]

These have been long-awaited as the last full edition was in 2004.

Important revisions include the use of tenofovir (TDF) in first line treatment (replacing d4T), more complex prophylaxis regimens and earlier treatment for pregnant women and universal treatment for infants <12 months of age.

The treatment guidelines are also summarised in an abridged version with a series of tables incorporating key recommendations from all three documents.

Management of adults and adolescents

When to start?

Antiretrovirals should be started in all HIV-positive patients with CD4 <200 cells/mm3 irrespective of clinical stage.

People with TB/HIV and pregnant women should start antiretroviral treatment at CD4 <350 cells/mm3. People with WHO stage 4 or DR TB should start treatment irrespective of their CD4 count.

What to start?

The recommended first line regimens for all new patients are:

• TDF+3TC or FTC+EFV
• TDF+3TC or FTC+NVP

Already receiving d4T-based regimen

If d4T is well tolerated patients should remain on this regimen. An early switch is recommended for any toxicity. People at high risk for toxicity (high BMI, low Hb, older female) should switch d4T for TDF.

Fast track

Pregnant women indicated for treatment, people with very low CD4 (<100 cells/mm3) and stage 4 with CD4 count not yet available and those with MDR/XDR TB, should be fast tracked ie start ART within two weeks of being eligible.

When to switch

Virlogical failure (>1000 copies/mL) over 3 months despite adherence interventions.

Second-line ART

Failing on d4T-based regimen:

• TDF+3TC or FTC +LPV/r

Failing on a TDF-based regimen:

• AZT+3TC+LPV/r

Third-line ART

Specialist referral where possible, but maintain on a failing regimen.

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That these guidelines did not adopt <350 cells/mm3 as the threshold for starting treatment for all, in line with the WHO, the Southern African Clinicians Society and many national guidelines, has raised much discussion. [2 ] Arguably this consideration may be largely academic in a country where the median CD4 count at initiation is still about 100 cells/mm3 despite a massive scaling up of testing. [3]

However, now that the SA Ministry of Health is about to launch a campaign to test 15 million people by June next year, this situation is likely to change. Earlier treatment for select groups and fast track for those most at risk however are very welcome.

An important change is the replacement of d4T with TDF for first-line regimens. As well as following guidance to avoid the more dramatic effects of lactic acidosis, hopefully “well tolerated” and “early switch” will be interpreted in the very best interests of patients who have endured peripheral neuropathy or lipoatrophy associated with this drug.  Equally dropping ddI from second-line regimens, though not affecting such large numbers of people, is a vast improvement.

Prevention of mother to child transmission

These guidelines make recommendations for pregnant women both eligible and ineligible for treatment and for infant feeding.

When to start?

As above, CD4 <350 cells/mm3.

What to start?

TDF+3TC or FTC +NVP

Women already receiving ART should substitute EFV with NVP if in first 12 weeks of pregnancy. Women contraindicated to TDF should receive AZT+3TC+NVP.

Prophylaxis for women CD4 >350 cells/mm3

AZT from 14 weeks + single dose NVP + AZT three hourly during labour; TDF+FTC single dose post delivery.

Infant regimens

Breast fed or formula fed infants of mothers on HAART: NVP at birth and daily for 6 weeks.

Breast fed or formula fed infants of mothers receiving prophylaxis: NVP at birth and daily for 6 weeks if formula fed or until cessation of breast feeding.

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Guidance for pregnant women is broadly similar to WHO recommendations. However, the approach to use of efavirenz is far more cautious. Whereas the WHO interpreted the low quality, conflicting evidence for the risks of in utero exposure to confine the contraindication to the first trimester, these guidelines do not recommend its inclusion at all in pregnancy.  From an operational point of view this will make treatment of pregnant women a bit more complicated and inconsistent with general adult recommendations. Efavirenz has a number advantages where simplification is important, it can be taken once daily in a fixed dose combination with TDF and FTC, unlike nevirapine there is no extra monitoring for rash and/or hepatoxicity risk and it can be used in conjunction with TB treatment.

The choice of a single dose of TDF/FTC “tail” coverage is an interesting one, whereas the WHO recommend 7 days of 3TC/AZT and this has been adopted by several national programmes, some have suggested that this may be too complicated to implement.

Chi et al showed a reduction in resistance using a single dose of TDF/FTC from approx 30% to 14% among women with CD4 cell counts of about 475 cells/mm3 receiving single dose nevirapine (women with CD4 <200 cells/mm3 were excluded and received HAART), of which approximately 80% received antepartum AZT for a median of about 37 days, and 30% had undetectable viral load at delivery. [4]

It is likely that a treatment threshold of <350 CD4 cells/mm3 will further exclude women most at risk for NNRTI resistance and this approach may offer a reasonable compromise between reduction of resistance risk and ease of implementation.

Management of HIV in children

When to start?

• Universal treatment for infants <12 months old.
• Clinical stage 3 or 4 or CD4 <25% or absolute CD4 <750 cells/mm3 for children age 1-5 years.
• Clinical stage 3 or 4 or CD4 < 350 cells/mm3 for children >5 years to 15 years.

What to start?

• Infants and children <3 years old: ABC+3TC+LPV/r.
• Children >3 years old: ABC+3TC+EFV.

Second line

Children >3 years old failing ABC+3TC+EFV: AZT+ddI+LPV/r

Children >3 years old failing an AZT- or ddI-based regimen: ABC+3TC+LPV

Children failing a LPV/r-based regimen and/or  <3 years old who are failing first-line require specialist referral.

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Universal treatment for infants <12 months old and initiation at CD4 350 cells/mm3 for children >5 years old reflects current international consensus. Treatment for children between 1 and 5 years has little data to guide us, and WHO and national guidelines all give slightly different recommendations.

That the threshold for initiation for children and adolescents between 5 and 15 years old is 350 cells/mm3 for all differs from adult recommendations, where a considerable number of people will not be eligible for treatment until CD4 drops to 200 cells/mm3.

References

1. SA Dept of Health. The South African Antiretroviral Treatment Guidelines, 2010.

http://www.sanac.org.za/resources/art-guidelines

2. WHO. New HIV recommendations to improve health, reduce infections and save lives. (01 December 2009).

http://www.who.int/mediacentre/news/releases/2009/world_aids_20091130/en/index.html

3. Geffen N. Guidelines on when to start treatment in resource poor settings. HTB, October 2009.

http://i-base.info/htb-south/190

4. Chi BH et al. Single-dose tenofovir and emtricitabine for reduction of viral resistance to non-nucleoside reverse transcriptase inhibitor drugs in women given intrapartum nevirapine for perinatal HIV prevention: an open-label randomised trial. Lancet. 2007 Nov 17;370(9600):1698-705. Epub 2007 November.

http://www.ncbi.nlm.nih.gov/pubmed/17997151

Other recommendations include provider initiated TB testing, and drug susceptibility testing (DST) for all previously treated TB patients at or before the start of treatment.

All HIV-positive patients with active TB should receive antiretrovirals.

World Health Organisation. Treatment of tuberculosis guidelines. Forth edition:

http://www.who.int/tb/publications/tb_treatmentguidelines/en/index.html

Advances in the treatment of HIV infection with antiretroviral therapy have led to dramatic reductions in opportunistic infections and death.  However, late presentation of HIV remains a problem and is a significant contributory cause to death in HIV-positive persons in the UK.  Furthermore, a recent UK Health Protection Agency (HPA) analysis showed that of 46,700 patients with diagnosed HIV, 19% had CD4 counts <200 cells/mm3 and therefore remain at significant risk of opportunistic infection.

These guidelines have been drawn up to help physicians investigate and manage HIV-positive patients suspected of, or having an opportunistic infection (OI).  The early chapters consider the most common presentations of OI disease such as respiratory, gastrointestinal and neurological disease.  Then follow specific organisms such as Candida spp, herpes simplex virus and varicella zoster virus. Finally, special circumstances including pregnancy, the use of the intensive care unit, fever of undetermined origin and management of imported infections, are also addressed.

Each section contains information on the background, epidemiology, presentation, treatment and prophylaxis of OIs.  Further information on the role of antiretroviral therapy is also discussed (see below).

The Guidelines Writing Group is grateful for all comments, which will be reviewed before publication.

http://www.bhiva.org

At the end of November 2009 the WHO released three Rapid Advice documents to guide HIV treatment and prevention strategies. [1]

The documents were:

• Antiretroviral therapy (ART) for adults and adolescents [2]
• Treatment for pregnant women and prevention of infant infection [3]
• Infant feeding [4]

Rapid advice: antiretroviral therapy for adults and adolescents

Since the last guideline revision in 2006, new evidence has become available, particularly concerning the earlier initiation of therapy. This document makes key recommendations in eight areas.

1. When to start?

Antiretroviral therapy should be started in all patients with <=350 CD4 cells/mm3 and with WHO clinical stage 3 and 4. (CD4 testing is required to identify patients with WHO clinical sage 1 and 2 who need to start treatment).

2. What to start

The recommended first line regimens are:

• AZT+3TC+efavirenz (EFV)
• AZT+3TC+nevirapine (NVP)
• TDF+3TC or FTC+NVP
• TDF+3TC or FTC+NVP

3. ART for HIV/TB co-infection

ART should be started in all HIV-positive people with active TB. TB treatment should be commenced first and followed by ART as soon as possible. EFV is the preferred NNRTI.

4. ART for HIV/HBV co-infection

ART should be started in all HIV-positive people needing treatment for their HBV. Regimens should contain dual-HBV therapy including tenofovir (TDF) plus 3TC or FTC.

5. ART for pregnant women

Recommendations for when to start and what to start with are as for a non-pregnant adult except that they do not recommend using efavirenz during the first trimester of pregnancy.

6. When to switch?

Where available they recommend viral load to confirm treatment failure (defined as persistently above 5000 copies/mL) and if this is available routinely, 6 month monitoring. Where viral load is not available they recommend use of immunological criteria to confirm treatment failure.

7. Second-line ART

Atazanavir/r (ATV/r) or lopinavir/r (LPV/r) are the recommended boosted PIs for second-line regimens. If d4T or AZT was used first-line, tenofovir plus either 3TC or FTC are recommended. If TDF was used first-line, then AZT+3TC or FTC.

8. Third-line regimens

This recommendation is not specific. New drugs such as integrase inhibitors and second generation NNRTIs and PIs are suggested. People on failing second line regimen with no available options are recommended to continue with that regimen.

comment

These guidelines are produced to inform national providers of the best standard of clinical care. In aspects that are currently aspirational, guidance is included on how to change from existing practice, for example in moving from using d4T to alternative drugs.

Two clinical questions not addressed are:

1. Whether lopinavir/r (Kaletra/Aluvia) monotherapy may have an important role in second-line regimens, given the supportive data from several studies? This would reduce cost and RTI-associated toxicty from drugs that may only provide limited antiretroviral activity, especially if nucleoside resistance developed on first-line treatment. This could provide some support for future third-line treatment, when CCR5 and integrase inhibitors become available.
2. Whether the recommendation to select a high cut-off for virological switching (>5000 copies/mL) might result in an unecessarily high risk of accumulating resistance to first-line drugs. As viral load monitoring is sometime only 6-monthly, this could delay a more protective earlier switch. Viral load blips have been reported up to 2000 copies/mL, though are usually lower, so deciding a true virological rebound at 2000 copies/mL may be worth considering in order to protect future options.

Rapid advice: treatment for pregnant women and prevention of infant infection

Again, this Rapid Advice was informed by new data particularly showing the benefit of starting ARV prophylaxis earlier in pregnancy and extended prophylaxis to mothers or infants is effective in reducing transmission during breastfeeding. They noted, “For the first time there is enough evidence for WHO to recommend ARVs while breastfeeding.”

The document addresses women who were both eligible and ineligible for ART for their own health and makes seven key recommendations.

1. As described in 5 above.
2. Eligible pregnant women should start ART irrespective of gestational age and continue throughout pregnancy, delivery and then indefinitely.
3. The preferred regimens for women eligible for treatment are:
   • AZT+3TC+NVP
   • AZT+3TC+EFV

   Alternative regimens are:
   • TDF+3TC(or FTC)+NVP
   • TDF+3TC (or FTC)+EFV

4. Infants of mothers receiving ART for their own health should receive:
   a. Daily NVP from birth until 6 weeks of age if breastfed.
   b. Daily AZT or NVP from birth until 6 weeks of age if not breastfed.
5. Women not eligible for ART for their own health should receive an ARV prophylaxis strategy. This should be started from as early as 14 weeks gestation or as soon as possible for women presenting later.
6. ARV maternal prophylaxis option A:
   • Antepartum daily AZT
   • Single dose NVP from onset of labour
   • AZT+3TC during labour and delivery
   • AZT+3TC 7 days postpartum
   Breastfed infants should receive daily NVP throughout the period and one week after breastfeeding. Non –breastfeeding infants should receive daily AZT +NVP from birth to 6 weeks of age.
7. ARV maternal prophylaxis option B:
   • AZT+3TC+lopinavir/r (LPV/r)
   • AZT+3TC+abacavir (ABC)
   • AZT+3TC+efavirenz (EFV)
   • TDF+FTC+efavirenz (EFV)
   Breastfed infants should receive daily NVP from birth until 6 weeks of age. Non –breastfeeding infants should receive daily AZT +NVP from birth to 6 weeks of age.

Options A and B are summarised in Table 1.

Table 1. ARV prophylaxis options recommended for HIV-infected pregnant women who do not need treatment for their own health

comment

The recommendations regarding the use of nevirapine and efavirenz are important in the new guidance for pregnant women. That the recommendations give high value to maternal health and the benefit that this has on transmission to her infant is most welcome. In the remarks in the guidelines it is noted that this also places relatively low value on the potential toxicity risks for the mother and unborn infant.

The adult ART guidance document highlights the low quality, conflicting evidence on the risks of efavirenz causing neural tube defects and that the overall rates of birth defects reported for efavirenz, nevirapine, lopinavir/r or tenofovir appear to be similar and also similar to rates reported for the general population. Initiation of efavirenz is not recommended in the first trimester and they remark that since the neural tube closes in the first 28 days and very few pregnancies are recognised by this time, the actual risks of starting efavirenz in the first trimester are hard to estimate.

Their review of nevirapine safety in pregnant women with CD4 counts 250-350 cells/mm3 did not confirm an elevated risk of serious side effects so the WHO panel concluded the benefits of using nevirapine in this situation outweigh the risks of not initiating ART.

This panel was unable to conclude whether it was better to use efavirenz or nevirapine in pregnant women after the first trimester and with higher or unknown CD4 cell counts and they added that over half the panel preferred efavirenz in these situations.

These recommendations will make things a lot easier from a programmatic point of view, whether national guidelines will follow suit remains to be seen.

Rapid advice: infant feeding in the context of HIV

This is a set of revised principles and recommendations intended for policy makers, academics and health workers in resource limited settings to assist national infant feeding strategies and implementation, in the context of HIV.

They draw on and further elaborate the revised WHO recommendations for ARVs to prevent mother to child transmission and in particular to prevent postnatal transmission through breastfeeding, which they describe as a major breakthrough that should contribute to improved child survival.

Key principles include:

1. Balancing HIV prevention with protection from other causes of child mortality. This principle recognises the association between maternal health and child survival.
2. Integrating HIV interventions into maternal and child health services. This should include CD4 testing and appropriate antiretroviral therapy or prophylaxis for the mothers’ health and/or to prevent MTCT.
3. Setting national recommendations for infant feeding in the context of HIV. Either breastfeeding with antiretroviral interventions or avoid all breastfeeding.
4. Informing mothers, known to be HIV positive about infant feeding alternatives.
5. Providing services to support mothers to feed their infants appropriately.
6. Avoiding harm to infant feeding practices in the general population.
7. Advising mothers who are HIV-negative to breastfeed on ways to remain HIV-negative: and mothers of unknown status should be offered HIV testing.
8. Investing in improvements in infant feeding practices in the context of HIV.

Key recommendations:

1. Making sure HIV-positive mothers receive the treatment and care they need to reduce transmission through breastfeeding in accordance with the WHO guidelines.
2. Mothers should exclusively breastfeed for the first six months and introduce appropriate complimentary foods thereafter and continue breastfeeding for the first 12 months of the infant’s life.
3. Stopping breastfeeding should occur gradually over one month and abrupt stopping is not recommended. Mothers who have been receiving prophylaxis should continue for one week after breastfeeding stops.
4. If mothers stop breastfeeding at any time formula or expressed, heat treated-breastmilk.
5. Conditions must be AFASS – affordable, feasible, acceptable, sustainable and safe to safely formula feed.
6. Heat treated expressed milk may be considered as an interim strategy in some circumstances such as an infant with low birthweight who cannot breastfeed, if the mother is unwell or antiretroviral drugs are not available.
7. Mothers are strongly encouraged to breastfeed infants known to be infected, exclusively for the first 6 months and then continue as recommended for the general population

comment

The most interesting recommendation is mixed feeding for infants 6-12 months of age. The panel remarked that transmission risk previously considered to be associated with this strategy should diminish with antiretroviral interventions. They also suggest that this may avoid many of the complexities associated with stopping breastfeeding and providing a safe and adequate diet to the infant during this period. This was considered a major advantage.

References:

1. World Health Organization HIV Treatment Recommendations. New HIV recommendations to improve health, reduce infections and save lives. (1 Dec 2009)
   http://www.who.int/mediacentre/news/releases/2009/world_aids_20091130/en
2. World Health Organization. Rapid advice: antiretroviral therapy for HIV infection in adults and adolescents. November 2009.
   http://www.who.int/hiv/pub/mtct/advice/en
3. World Health Organization. Rapid advice: use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. November 2009.
   http://www.who.int/hiv/pub/mtct/advice/en
4. World Health Organization. Rapid advice: infant feeding in the context of HIV.
   http://www.who.int/hiv/pub/paediatric/advice

Changes are highlighted in yellow on the PDF file and include:

New section

Based on interests and requests from HIV practitioners, a new section entitled “Considerations in Managing Patients with HIV-2 Infection” has been added to the guidelines. This new section briefly reviews the current knowledge on the epidemiology and diagnosis of HIV-2 infection and the role of antiretroviral therapy in the management of patients with HIV-2 mono-infection and HIV-1/HIV-2 coinfection.

Key updates

Drug resistance testing: In this revision, the Panel provides more specific recommendations on when to use genotypic versus phenotypic testing to guide therapy in treatment-experienced patients with viremia while on treatment.

• Genotypic testing is recommended as the preferred resistance testing to guide therapy in patients with suboptimal virologic responses or virologic failure while on first or second regimens (AIII).
• Addition of phenotypic testing to genotypic testing is generally preferred for persons with known or suspected complex drug resistance mutation patterns, particularly to protease inhibitors (BIII).

Initiation of antiretroviral therapy: In this updated version of the guidelines, the Panel recommends earlier initiation of antiretroviral therapy with the following specific recommendations:

• Antiretroviral therapy should be initiated in all patients with a history of an AIDS-defining illness or with CD4 count < 350 cells/mm3 (AI).
• Antiretroviral therapy should also be initiated, regardless of CD4 count, in patients with the following conditions: pregnancy (AI), HIV-associated nephropathy (AII), and hepatitis B virus (HBV) coinfection when treatment of HBV is indicated (AIII).
• Antiretroviral therapy is recommended for patients with CD4 counts between 350 and 500 cells/mm3. The Panel was divided on the strength of this recommendation: 55% of Panel members for strong recommendation (A) and 45% for moderate recommendation (B) (A/B-II).
• For patients with CD4 counts >500 cells/mm3, 50% of Panel members favor starting antiretroviral therapy (B); the other 50% of members view treatment as optional (C) in this setting (B/C-III).

Patients initiating antiretroviral therapy should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers may elect to defer therapy, based on clinical and/or psychosocial factors on a case-by-case basis.

What to start in antiretroviral-naïve patients

Increasing clinical trial data in the past few years have allowed for better distinction between the virological efficacy and safety of different combination regimens. Instead of providing recommendations for individual antiretroviral components to use to make up a combination, the Panel now defines what regimens are recommended in treatment naive patients.

Regimens are classified as “Preferred,” “Alternative,” “Acceptable,” “Regimens that may be acceptable but more definitive data are needed,” and “Regimens to be used with caution.

The following changes were made in the recommendations:

• Raltegravir + tenofovir/emtricitabine” has been added as a “Preferred” regimen based on the results of a Phase III randomised controlled trial (AI).
• Four regimens are now listed as “Preferred” regimens for treatment-naïve patients:
  i) efavirenz/tenofovir/emtricitabine;
  ii) ritonavir-boosted atazanavir + tenofovir/emtricitabine;
  iii) ritonavir-boosted darunavir + tenofovir/emtricitabine; and
  iv) raltegravir + tenofovir/emtricitabine.
• Lopinavir/ritonavir-based regimens are now listed as “Alternative” (BI) instead of “Preferred” regimens, except in pregnant women, where twice-daily lopinavir/ritonavir + zidovudine/lamivudine remains a “Preferred” regimen (AI).

Additional updates

The following sections and their relevant tables have been substantially updated:

• What not to use
• Management of treatment-experienced patients
• Treatment simplification
• Hepatitis C coinfection
• Antiretroviral-associated adverse effects
• Antiretroviral drug interactions
• Preventing secondary transmission of HIV

These and other DHHS guidelines are available on the NIH aidsinfo website
http://www.aidsinfo.nih.gov

Direct download (PDF):
http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

comment

The main concern in these guidelines is the strength of the statement for new recommendations for starting treatment.

Currently the document states that the whole panel recommends starting treatment for people with a CD4 count 350-500. This leaves no indication of support for the view that there is insufficient data to balance the risks against the benefits.

Although this is discussed in the main document in more detail, the summary of the guidelines does not accurately reflect the later discussion. The summary is far more widely read than the entire document, and it would therefore be helpful for this wording to be reconsidered.

This years recommendations are especially important as they coincide with the enrollment of the NIH-funded START study which may be the only opportunity to look at both the risks and benefits from a randomised study.

So while there is data supporting short-term safety, there is no data based on long-term risk.

An example of risk comes from the trials of the preferred regimens referenced with the latest data (STARTMRK, ARTEMIS etc). Viral suppression to <50 copies/mL (the primary goal of treatment) was not achieved by around 15% patients at 48 weeks and 20% by week 96. In the context of lifelong treatment, low levels of resistance currently reported, may become more serious if second-line treatment also fails. Population-based uptake of treatment in Western countries is also frequently associated with higher rates of failure.

A second example is that no combination has been shown not to cause fat accumulation, itself associated with additional longer-term health complications, as well as reduced quality of life. This complication may also be related to race and gender.

These potential risks from earlier treatment are not addressed in the main guidelines.

In addition, while the summary states that ‘some people may defer treatment’, this is suggested for ‘clinical or psychosocial factors’ and is tied to an earlier sentence about people who might have difficulty with adherence.

While the document is only produced as guidance, the DHHS guidelines are widely interpreted as indicating the minimum recommended standard of care, based on the best available evidence. Clinical trials, especially NIH funded trials, become unethical if they recommend less that the current standard of care for any participant.

While many clinicians, researchers and advocates believe that there is still equipoise on the use of treatment by people with counts 350-500, the current summary brings them into conflict with what are otherwise, one of the most useful documents for the management of HIV infection.

Given the summary has already been widely distributed and publicised, it would help if any subsequent update addresses whether a randomised trial in people with CD4 counts lower than 500 cells/mm3 remains ethical. Currently the guideline summary states that expert opinion believes that further research is unnecessary.

This is important in the context of the START trial which is just enrolling patients and which will be the most important study to inform on this and many other questions.

The history of previous recommendations from the DHHS panel on the when treatment should be started shows the importance of collecting evidence from a randomised study. Earlier recommendations to start at 500 and 350 have probably resulted in widespread complications from side effects and resistance.

Other changes in the guidelines are positive, especially the inclusion of a new section on HIV-2.

The updated PENTA guidelines were published in the November 2009 edition of HIV Medicine. These guidelines offer practical recommendations for treating children with HIV in Europe.

The main changes since the 2004 guidelines are:

When to start?

Universal treatment is recommended as soon as possible after diagnosis for all infants less than 12 months of age. The guidelines stress particular urgency for infants infected despite prevention of mother to child transmission (PMTCT).

For children 12 months or older, HAART should be started in all symptomatic cases (CDC stage B or C, WHO stage 3 or 4). Children 12 months or older with no or minor symptoms (CDC stage A or N or WHO stage 1 or 2) treatment should be started when CD4 count or percentage falls below the following thresholds:

• 1 to <3 years: CD4<25% or 1000 cells/mm
• 3 to <5 years: CD4<20% or <500 cells/mm3
• Above 5 years: CD4 count <350 cells/mm3

These treatment thresholds differ significantly from the 2004 guidelines, see Table 1 for comparison of PENTA guidelines 2004 and 2009. Some recommendations also differ from the WHO and US treatment thresholds, see Table 2 comparison of PENTA, WHO and US treatment thresholds.

In children aged more than 12 months with no or minor symptoms and CD4 counts or percentages above these thresholds, HAART should be considered if the viral load exceeds 100,000 copies/mL.

Table 1: Comparison of PENTA guidelines 2004 and 2009

Table 2: Comparison of current PENTA, WHO and US treatment thresholds

What to start with?

The guidelines recommend a regimen of two NRTIs and either an NNRTI or a boosted PI for ARV-naïve children with no evidence of resistance. They note that a PI may be preferred in children with anticipated poor adherence.

Abacavir and 3TC are recommended for children who are HLA-B *5701 negative and AZT and 3TC for those who are HLA-B *5701 positive.

Nevirapine is recommended for children <3 years and efavirenz for older children.

Lopinavir/ritonavir is recommended for young children. For older children alternative boosted PIs may be used, including fosamprenavir/r and duranavir/r which are licensed for children from 6 years, atazanavir/r (which is licensed in the US for children from 6 years but not in Europe) and saquinavir/r (which is not licensed for children but may be suitable for adolescents.

Other recommendations

Recommendations on the use of resistance testing, TDM and HLA testing are informed by adult data and paediatric cohorts in Europe.

The guidelines highlight the paucity of data from RCTs on which to base recommendations for children and note that available trials tend to be small, therefore “… we continue to rely on cohort studies, extrapolation from adult data and expert opinion.” They recommend that wherever possible children should be enrolled in clinical trials.

Drug information will be available alongside the guideline, and will be kept updated, on the PENTA website www.pentatrials.org

comment

WHO paediatric guidance is due for update imminently, and is likely to recommend earlier treatment in line with updated WHO adult guidance.

WHO and PENTA will provide different recommendations based on the same data. This reflects both the paucity of high quality evidence from randomised clinical trials, on which the guidelines are based, and that PENTA guidelines are intended for use in Europe while WHO guidelines will predominantly inform national guidelines in less well resourced countries, where the ability of treatment programmes to deliver care may also be an issue.

We intend to summarise and review new WHO paediatric guidance later in 2010 when it is published. PENTA guidelines are not likely to change when new WHO paediatric guidance is published, and remain the current recommendations for treating children with HIV in Europe.

Ref: PENTA Steering Committee. PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric infection. HIV Medicine 2009, 10, 591-613.

The appropriate CD4 count to initiate treatment is a topic of much research and discussion. In South Africa, the threshold in the public health system remains 200 cells/mm³, based on the Department of Health guidelines published in 2004.[1] In the private sector, medical schemes are generally using a threshold of 350 cells/mm³, based on the Southern African HIV Clinicians Society Guidelines. [2] Other sub-Saharan African generally use a 200 threshold as well. Meanwhile, Europe and North America also initiate at first CD4 count below 350 cells/mm³.

The 350 cells/mm³ threshold is supported with evidence from several studies:

The When to Start Consortium, in an analysis of 15 cohort studies, found a greater than two times hazard ratio for progression to AIDS or death in people with CD4 counts from 100 to 200 cells/mm³ compared to people with CD4 counts of 201 to 300 cells/mm³ (HR: 2.21; 95%CI 1.91-2.56). There was also a significant difference in progression between the CD4 count strata of 151-250 cells/mm³ and 251-350 cells/mm³ (HR:1.71; 95%CI 1.43-2.04). (See HTB South April-June 2009.) [3] Also see Kitahata et al., which found a 1.69 [95%CI: 1.26-2.25] greater risk of death in patients who started treatment with a CD4 count between 350 and 500 cells/mm³ versus patients who deferred. [4]

The CIPRA HT 001 study was started in Port-au-Prince, Haiti in 2005. The 816 volunteers with CD4 counts between 200 and 350 cells/mm³ were randomised to either start HAART immediately or defer until their CD4 counts dropped to below 200 cells/mm³, the current standard of care in Haiti. The DSMB stopped the trial in May 2009 when it found clear evidence favouring the earlier treatment group. In the immediate group six people died versus 23 in the deferred group. Twice as many people (36 vs 18) contracted TB in the deferred group. These results, according to NIAID, are statistically significant. [5]

The START trial will answer the question as to whether treatment should be initiated at CD4 counts > 500 cells/mm³ or when it drops to below 350 cells/mm³. The trial began this year, but its estimated completion date is March 2015. In the meanwhile guideline developers need to make decisions based on the best, albeit incomplete, evidence available.

Francois Venter’s presentation at IAS2009

Francois Venter presented six issues affecting the discussion on when to start at a symposium at IAS2009. [6]

First, he presented the currently available evidence and ongoing trials to determine the appropriate CD4 count initiation threshold. He contrasted this with data presented by Matthias Egger at CROI 2007 that reviewed 176 sites from 2003 to 2005 in 42 countries that included 33,000 patients and showed when people actually are starting HAART.[7] In developed countries, the average patient initiates treatment with a CD4 count of 150 to 200 cells/mm³. In Sub-Saharan Africa, it has increased from 50 cells/mm³ to about 100 cells/mm³. Venter pointed out that this was despite a large increase in testing in South Africa over the same period, with only about 20% of tested patients eligible for HAART according to current guidelines.[8] In Venter’s programme in the inner city of Johannesburg, the average CD4 count at initiation is 106, despite 70% coverage and a massive escalation in testing. He stressed that retaining patients who have been tested in care is the key challenge as opposed to escalating testing.

Secondly, he explained that many people die waiting for treatment. For example, of 4570 patients followed up for at least one year in a cohort in Free State Province, South Africa, 53.2% died. Of these, 87% died before receiving HAART. [9] Venter presented data from Braitstein and colleagues showing that expedited care reduced mortality by 60%.

Third, he considered whether treatment should start earlier to reduce non-AIDS morbidity and mortality. He presented data from Andrew Phillips and colleagues that examined the risk of non-AIDS events in four studies: Flexible Initial Retrovirus Suppressive Therapies (FIRST) trial, Data Collection on Adverse Events of Anti-HIV Drugs study (DAD), Concerted Action on SeroConversion to AIDS and Death in Europe collaboration (CASCADE) and the Strategies for Management of Antiretroviral Therapy (SMART) trial.

The adjusted relative hazards for the effect of CD4 cell count on the risk of liver disease was significant in DAD, CASCADE and SMART. For non-AIDS cancer, it was significant in FIRST, DAD and CASCADE. For renal disease it was significant in FIRST and DAD (not measured for CASCADE) and for cardiovascular disease it was significant in CASCADE. In all comparisons, even when the results were not significant for a particular study, higher CD4 counts were correlated with less disease. Venter demonstrated that these results are relevant to South Africa by pointing out that there are overlapping epidemics of obesity and HIV in South Africa. He noted the high prevalence of hypertension and diabetes and suggested this put HIV-positive people in South Africa at high risk of dying from non-AIDS illnesses at low CD4 counts.

Fourth, he considered the effect of earlier HAART on opportunistic infections. There are high rates of opportunistic infections above CD4 counts of 200 cells/mm³ in resource poor settings. For example, an analysis by Badri and colleagues compared the six-monthly risk of death according to CD4 count and WHO stage. They found that the risk of death for WHO stages 1 and 2 was 3.5% (95%CI 1.4-7.1) for people with less than 200 cells/mm³, 2.8% (95%CI 1.3-5.3) for 200 to 350 cells/mm³ and 1.2% (0.5-2.3) for greater than 350 cells/mm³. For WHO stage 3 the death rates were 10.1% (95%CI 7.5-13.2) for <200 cells/mm³, 4·3% (95%CI 2.1-7.8) for 200 to 350 cells/mm³, and 4.9% (95%CI 2.3-9.1) for > 350 cells/mm³. For WHO stage 4, 22.2% (95%CI 17.9-27.1) for < 200 cells/mm³, 10.3% (95%CI 3.5-22.4) for 200 to 350 cells/mm³, and 13.8% (95%CI 4.1-32.6) for >350 cells/mm³. Interestingly, 52% of deaths took place in patients without AIDS. [10]

Venter pointed out the additional concerns in resource-poor settings about opportunistic infections. This has been well characterised for tuberculosis (see HTB South July to September 2009, pp. 22-28). But there are also concerns about greater risk of other bacterial (and fungal) infections including cryptococcal meningitis, pneumococcus, salmonella, wasting and malaria, even at higher CD4 counts. Cryptococcis is a particularly important concern. For example, a study by Olivier Lortholary and colleagues found that the mortality rate per 100 person-years was 15.3 [95%CI: 12.2-18.4] in the HAART era versus 63.8 [95%CI: 53.0-74.9] in the pre-HAART era for people diagnosed with this infection. [11] A study in Thailand by Jongwutiwes and colleagues retrospectively analysed 149 patients with cryptococcis. The cumulative 75% survival from relapse duration was over 10 months amongst those who did not receive HAART versus 42 months in those who did (p<0.01). [12]

Fifth, Venter considered maternal HAART and paediatric treatment. He examined the CHER results (discussed extensively in several issues of HTB ) which led to the WHO guidelines recommendation of universal treatment for all HIV-infected infants younger than 12 months. [13,14] Although mortality on the immediate treatment arm of CHER was as low as 4%, Venter pointed out that in 2007, only 8% of HIV-exposed infants were tested in the first two months of life. Using data from Malawi, he showed that the vast majority of children entered HIV care via hospital wards, as opposed to PMTCT follow-up, VCT and child health institutions, indicating systemic problems with getting HIV-infected children onto early treatment. Venter stated that it was better to prevent paediatric infection in the first place and that it was much easier to treat mothers than babies.

Venter considered the pros and cons of universal treatment for pregnant women, summarised in Table 1. He also emphasised the need for universal treatment for pregnant women with CD4 counts < 350 cells/mm³, citing data from Louise Kuhn shown in her plenary talk at IAS2009 that in the ZEBS study 84% of maternal deaths and 82% of postnatal infections occur in women with CD4 counts < 350 cells/mm³ (cf < 200 cells/mm³ at which 55% of maternal deaths and 47% of postnatal infections occur). [15]

ADD TABLE

Table 1: Pros and cons of universal treatment for pregnant women

Finally Venter considered the effect of earlier treatment on prevention. He pointed out that prevention programmes have had disappointing results and asked whether reducing viral load earlier might have a public health impact. He said there could be a convenient convergence of using HAART for both treatment and prevention purposes.

Venter concluded by pointing out that so long as stavudine is part of the standard care in Sub-Saharan Africa, earlier treatment would be harder to implement. The drug is in wide use. Venter presented data from Westreich and colleagues showing that stavudine is used by over 80% of Zambian, Mocambican and Tanzanian HAART patients and over 70% of Côte d’Ivoire ones. That study analysed a cohort of over 7,000 patients in Johannesburg. It found that for ongoing TB treatment at HAART initiation, the risk (adjusted hazard ratio) of a stavudine switch (compared to not being on TB treatment) was 3.18 (95%CI: 1.82-5.56) in the first 2 months of HAART, 2.51 (95%CI: 1.77-3.54) in months 3 to 6, and 1.19 (95%CI: 0.94-1.52) thereafter. For concurrent initiation of TB and HAART treatment, the risk was 6.60 (95% CI: 3.03-14.37) in the first 2 months, 1.88 (95%CI: 0.87-4.09) in months 3-6, and 1.07 (95%CI: 0.65-1.76) thereafter. There was no effect on the risk of stavudine substitution if patients were treated for TB after they had initiated HAART. [16]

In a study from a programme in Kigali Rwanda published by MSF researchers in September, stavudine side-effects were responsible for substantial switching. Out of 2190 adults followed up for a median of 1.5 years, stavudine was replaced in 175 patients (8.0%) for neuropathy, 69 (3.1%) for lactic acidosis and 157 (7.2%) for lipoatrophy. Lipoatrophy was the most frequent adverse event by three years of treatment. The authors concluded that stavudine is associated with significant long-term toxicity. They suggested stavudine-dose reduction, increased access to safer HAART regimens in low-income countries and close monitoring for those at risk. [17]

Data from IAS2009 on drug switching due to stavudine is presented in another article in this issue titled ARV Programme Results: Reports at IAS.

Cost-effectiveness of 350 cells/mm³ initiation

A study by Walensky and colleagues, published in the Annals of Internal Medicine, has modeled the cost-effectiveness of three options: (1) no treatment, (2) treatment initiated at CD4 count less than 250 cells/mm³ and (3) treatment initiated at CD4 count less than 350 cells/mm³. The study found that initiating HAART in South Africa at 350 cells/mm³ will reduce morbidity and mortality, improve long-term survival, and be cost-effective compared to initiation at 250 cells/mm³. The authors recommend that treatment guidelines should be changed to allow initiation when a patient’s CD4 count is below 350 cells/mm³. [18]

The objective of the study was to inform the crucial decision of when to start now, ie in the period before clinical trial results are published. Based on their results, the editors write, “Earlier antiretroviral therapy will probably prove to be superior in South Africa.”

In all scenarios, cotrimoxazole prophylaxis at a CD4 count < 500 cells/mm³ was modelled. The strategies were analysed over short-term (5 years) and life-time periods. Only direct HIV-associated uses of medical resources were considered.

The study used the CEPAC (Cost-Effectiveness of Preventing AIDS Complications) International model. All costs and life-expectancies were discounted at a rate of 3% per year. All monetary amounts were calculated using 2006 US dollars. The model has many input parameters, whose values were derived from clinical trials and observational studies in South Africa. Baseline at treatment parameters include mean age, ratio of men to women, mean CD4 count and distribution of the population over several HIV viral load strata. Parameters for modeling the onset of disease include monthly CD4 cell change (linked to viral load), monthly risk for severe opportunistic infection; efficacy of cotrimoxazole at reducing severe bacterial diseases, toxoplasmosis and PCP; monthly risk of HIV-related death and efficacy of HAART at viral load suppression by 48 weeks (broken down by first versus second-line treatment). In accordance with the South African treatment guidelines, the model provides for clinical assessments to occur every 3 months and CD4 and viral load testing every 6 months while receiving therapy.

The WHO considers an intervention cost-effective if it costs less than three times the per capita GDP to save one quality adjusted life-year. It considers an intervention very cost-effective if it costs less than the per capita GDP to save one quality adjusted life-year. However, the study examined years of life saved without adjusting for quality. Nevertheless, this is a minor difference and for practical purposes it is acceptable to directly compare the study’s findings with the WHO measures of cost-effectiveness. The cost-effectiveness of the study’s outputs was compared with the 2006 per capita GDP of $5,400 in South Africa.

The discounted per person lifetime cost for the strategies is $3,930 (no treatment), $12,730 (250 cells/mm³) and $13,620 (350 cells/mm³). Both treatment strategies would increase life-expectancy by at least 7.9 years over the no treatment strategy. Compared with no treatment, a treatment threshold CD4 count of 250 cells/mm³ would have an incremental cost-effectiveness ratio of $1,100 per life-year saved. And compared with a threshold of 250 cells/mm³, a threshold of 350 cells/mm³ would have an incremental cost-effectiveness ratio of $1,200 per life-year saved. (The incremental cost-effectiveness ratio is the additional cost of the intervention divided by the number of additional deaths prevented by the intervention.)

Table 2 summarises the clinical outcomes and costs over the next five years in the two treatment scenarios.

ADD TABLE

Table 2: Clinical outcomes and costs over the next five years in the treatment scenarios

Adapted from Walensky et al. (b = billion, m = million).

Using the WHO cost-effectiveness guidelines, the authors calculated that initiating treatment at a CD4 count of 350 cells/mm³ over the next five years should be used if the probability that a trial shows benefit for this threshold is 17% or greater.

The authors also conducted sensitivity analysis on the model’s lifetime projections and made the following findings:

1. Fewer than 39% of second-line patients initiated using a 350 cells/mm³ threshold would have to achieve viral suppression at 48 weeks to match the projected survival rate from using a threshold of 250 cells/mm³. This is a 32% relative decrease from the base case.

2. Discontinuation of care in the 350 cells/mm³ group (eg due to treatment fatigue) would have to be more than 19% to decrease survival compared to the 250 cells/mm³ group.

3. Including a hypothetical third-line regimen increased life-expectancy in both treatment groups.

COMMENT

The cost-effectiveness study by Walensky and colleagues presents a strong economic argument for changing the HAART guidelines in South Africa to treat everyone with a CD4 count < 350 cells/mm³. Shortly before their study was published, NIAID announced the termination of the CIPRA HT 001, arguably settling the question that 350 is a better threshold than 200 cells/mm³ (although the cost-effectiveness study compared 350 to 250 and not 200 cells/mm³).

Venter’s analysis provides an excellent summary of the complex issues affecting when to start. His presentation shows that systemic problems are at least as important as changing guidelines. Even in developed countries, many patients start late, ie well within guideline recommendations, and the situation in resource-poor areas is much worse.

Interestingly when asked at IAS2009, one of the CIPRA HT 001 study trial researchers explained that the median CD4 count for the immediate group was 280 cells/mm³ (IQR: approximately 230-300) versus 170 cells/mm³ for the deferred group. It is notable that even in a trial, people did not start close to the stated threshold but the difference between early versus delayed treatment was still profound.

Changing the CD4 threshold will not by itself remedy this situation. It is a positive development that more people are getting tested earlier for HIV, but if there is then nothing to offer them until they are ill, they are likely to be lost to follow up, only to reappear with very low CD4 counts. Ensuring that patients who are tested early and then retained in care is the key challenge and probably requires system changes.

Ironically, if the START study demonstrates that immediate HAART is better than deferred, then this might prove to be a useful mechanism for retaining people who have tested HIV-positive in the health system.

This should not detract from the need for effective public communications programmes that encourage early testing, or provider-initiated testing. It is just that these programmes would be more effective at keeping patients in the system.

The move towards earlier treatment has become possible because of improved medicines. But the long-term side effects of stavudine make it much harder to determine an appropriate threshold in programmes that use this drug. Venter’s concern about the widespread use of stavudine in sub-Saharan Africa can be alleviated if steps are taken to gradually replace it with tenofovir. As reported in the Treatment Update section of the previous issue of HTB South, there is at least one generic manufacturer making a low-cost 3-in-1 once-daily tenofovir containing fixed-dose combination pill that is WHO prequalified and FDA tentatively approved. Other generic manufacturers are intending to do the same. Surely these should become the standard first-line regimens in sub-Saharan Africa?

Discussions are underway, and it seems likely that 350 CD4 as a starting point and tenofovir in first line to replace d4T, will be added to South African guidelines. However, both of these come with significant extra costs. So qualifications may apply, at least initially.

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