WHO publish major revisions to HIV management guidelines (Nov 2009)
Polly Clayden, HIV i-Base
At the end of November 2009 the WHO released three Rapid Advice documents to guide HIV treatment and prevention strategies. 
The documents were:
- Antiretroviral therapy (ART) for adults and adolescents 
- Treatment for pregnant women and prevention of infant infection 
- Infant feeding 
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
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.
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:
i) 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.
ii) 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:
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-positive pregnant women who do not need treatment for their own health
|Option A: Maternal AZT||Option B: Maternal triple ARV prophylaxis|
|AZT from 14 weeks gestation sdNVP at onset of labout* AZT+3TC during labour and delivery AZT + 3TC 7 days
post partum *sd NVP can be omitted if mother receives >4 weeks of AZT post partum
|Triple ARV from 14 weeks until one week after all exposure
to breast milk has ended AZT+3TC+LPV/r AZT+3TC+ABC AZT+3TC+EFV TDF+FTC+EFV
Daily NVP from birth until one week after exposure to breast milk has ended
Non-breastfeeding AZT or NVP for 6 weeksBreastfeeding Daily NVP from birth to 6 weeks
Non-breastfeeding AZT or NVP for 6 weeks
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.
However, of particular importance to UK policy and clinical practice, they state: In highly resourced countries in which infant and child mortality rates were low, largely due to low rates of serious infectious diseases and malnutrition, HIV positive mothers are strongly and appropriately recommended to avoid all breastfeeding. In some of these countries, infants have been removed from mothers who have wanted to breastfeed despite being HIV positive and even being on ARV treatment. In these settings, the pursuit of breastfeeding in the presence of safe and effective alternatives may be considered to constitute abuse or neglect.
BHIVA will be issuing guidance as a response to these WHO recommendations for resource limited countries, which will continue to strongly recommend avoidance of breastfeeding for HIV positive women (and will be available at the upcoming BHIVA conference).
i-Base are preparing information for the community to use with our patient guides.
We will also review these recommendations in more detail in the next issue of HTB South.
- World Health Organization HIV Treatment Recommendations. New HIV recommendations to improve health, reduce infections and save lives. (1 Dec 2009)
- World Health Organization. Rapid advice: antiretroviral therapy for HIV infection in adults and adolescents. November 2009.
- World Health Organization. Rapid advice: use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. November 2009.
- World Health Organization. Rapid advice: infant feeding in the context of HIV.