Southern African HIV Clinicians' Society: new treatment guidelines

ART recommended for all with CD4 counts below 350, say South African doctors

Antiretroviral therapy should be recommended to all people with HIV who have CD4 cell counts below 350 cells/mm³ regardless of whether they have symptoms of HIV disease or not, according to new guidelines from the Southern African HIV Clinicians’ Society published in the Summer 2008 edition of the Society’s journal.

Current South African Department of Health guidelines recommend that treatment should start when the CD4 count falls below 200 cells/mm³, or when a person has WHO stage 4 symptoms, regardless of CD4 cell count.

The South African physicians’ recommendation on when to start treatment comes soon after similar recommendations in Europe, the United States and the United Kingdom, all endorsed by leading HIV specialists.

Although the guidelines will have no immediate effect on HIV treatment in the public sector, where Department of Health guidelines issued in 2003 prevail, the South African HIV Clinicians’ Society guidelines will be influential in the private sector,andwill be used to lobby for changes to public sector guidelines.

New first-line drugs recommended 

In first line treatment, efavirenz or nevirapine should be used alongside AZT/3TC, abacavir/3TC or tenofovir/FTC. 

The new guidelines do not recommend the use of stavudine (d4T) due to the high rates of toxicity seen with the drug. Stavudine may cause peripheral neuropathy, fat loss (lipoatrophy) and lactic acidosis. The latter is a life-threatening side-effect, and has been seen most frequently in women with high body mass.

“Public sector programmes are urged to consider dropping stavudine from first-line ART, or at least to make alternative NRTIs available in the case of toxicity,” the guidelines state. The World Health Organization recommended in 2006 that stavudine should be dropped from first-line regimens wherever possible.

The South African guidelines note that AZT is associated with lipoatrophy, but continue to recommend it as an option for first-line treatment. 

For second line therapy, the Southern African HIV Clinicians’ Society recommends the use of AZT/ddI or tenofovir/FTC, coupled with a protease inhibitor - either lopinavir or atazanavir or saquinavir boosted with low-dose ritonavir. 

AZT/ddI is recommended for use after tenofovir or abacavir-based first-line treatment, while tenofovir/FTC is recommended for use after AZT or d4T-based first-line treatment (although AZT/ddI may also be used after d4T-based first-line treatment). 

In patients with resistance to protease inhibitors, NNRTIs and nucleoside analogues, the guidelines recommend that in the absence of integrase inhibitors or newer protease inhibitors such as darunavir, currently unavailable in southern Africa, lopinavir/ritonavir should be used since it is likely to have the greatest activity against PI-resistant viruses. FTC or 3TC may also prove useful, since maintenance of the M184V mutation associated with these drugs impairs viral replication and is associated with lower viral load. There is no point in using efavirenz or nevirapine because they do not impair viral fitness. 

Pregnant women 

All pregnant women should receive three-drug antiretroviral therapy, regardless of CD4 cell count, the South African clinicians recommend. Their view directly contradicts the guidelines issued by South Africa’s Department of Health in February 2008, which also diverged from World Health Organization guidance by recommending seven days of AZT treatment for infants only, after single dose nevirapine for mother and child at the time of delivery. 

The Department of Health guidelines on prevention of mother to child transmission guidelines were condemned at the time by Southern African HIV Clinicians’ Society president Dr Francois Venter, who said that South Africa was a middle income country behaving like an economic basket case. 

The Southern African HIV Clinicians’ Society recommends that pregnant women should start treatment within two weeks of the first clinic visit if they have been adequately prepared regarding adherence and HIV status disclosure. However, treatment should not start in the first trimester of pregnancy unless a woman is seriously ill due to HIV, due to any possible harmful effects on the developing foetus. 

In women with a CD4 cell count below 250 cells/mm³, treatment during pregnancy should be based on nevirapine, but in women with CD4 counts above this level, a boosted protease inhibitor should be used due to the increased risk of hepatitis associated with nevirapine rash. 

After delivery, antiretroviral therapy should continue throughout the breastfeeding period. Women with CD4 counts below 350 should continue treatment indefinitely, while women with CD4 counts above 350 should stop when breastfeeding is discontinued. 

Women who are diagnosed with HIV around the time of labour, who are not receiving antiretroviral therapy, should receive single dose nevirapine at the onset of  labour, and AZT/3TC for one week after delivery to minimise the risk of NNRTI resistance caused by the very long half-life of nevirapine. 

ART and TB

TB can occur at a wide range of CD4 counts and is not an automatic indication for starting treatment unless is it extrapulmonary or disseminated. In order to reduce the risk of toxicity and immune reconstitution syndrome, the guidelines recommend:

• In those with CD4 counts below 200, ART should be started 2-8 weeks after starting TB treatment, when it is clear that TB treatment is tolerated and symptoms are improving.
• In those with CD4 counts between 200 and 350, ART should be delayed until after the 2-month intensive phase of TB treatment has been completed.
• CD4 above 350: defer ART.

Monitoring

When patients are preparing to start ART, they should undergo the following baseline tests:

• CD4 count
• Liver function: ALT may be sufficient.
• Full blood count
• Hepatitis B surface antigen.
• Serum creatinine to calculate creatinine clearance and urinalysis for proteinuria.

Whilst on treatment, the following monitoring should be carried out for all patients:

• With AZT: monitor full blood counts during first six months of treatment for anaemia.
• Hepatotoxicity: monitor ALT in patients receiving nevirapine at weeks 2, 4, 16 and then every three months. Any elevations with symptoms of hepatitis should be regarded as an indication to stop, and monitoring should take place weekly in people with ALT levels between 2.5 and 5 times the upper limit of normal. If ALT levels rise above five times the upper limit of normal, stop the drug presumed to be causing liver enzyme elevation; if above ten times the upper limit of normal, stop all antiretrovirals.
• Screen for active hepatitis B infection in all patients, and watch for hepatitis flares in patients with underlying hepatitis B or C due to immune reconstitution after starting treatment. Use tenofovir and 3TC or FTC in patients with hepatitis B, and continue this backbone if there is a need to switch to second-line therapy, since these are the only hepatitis B drugs available.
• Creatinine: if creatinine clearance is less than 50ml/min, tenofovir should be avoided and dosages of ddI, 3TC and d4T should be reduced; if below 10ml/min dosages should be further reduced. See US HIV Medicine Association guidelines for further details. 

Preparing for treatment

Patient readiness for therapy is as important as the medical indications for commencing therapy.

• Patient must demonstrate insight.
• Patient must be informed that lifelong therapy is essen­tial.
• Patient must be aware of importance of adherence.
• Patient must have been adequately informed about side-effects.
• Patient must have established the ability to attend reli­ably and have attended at least two or three visits before commencing therapy. 

Patients should be provided with information on the fol­lowing:

• ART as lifelong therapy.
• the importance of adherence
• side-effects of ART, and what to do if side-effects occur.

Active depression or substance abuse should be dealt with. Formulate a personal treatment plan, including drug storage and strategies for missed doses, with your pa­tient. Disclosure of HIV status should be strongly encouraged as this has been shown to be an important determinant of adherence. Patients should be encouraged to join a support group or identify a treatment ‘buddy’. Adequate counselling about safer sex practices must be provided to prevent transmitting to others or reinfection with a different strain.

Reference

Adult Guidelines Committee. Antiretroviral therapy in adults, January 2008. Journal of the Southern African HIV Clinicians Society, p18-31, 2008.