British HIV Association recommendations

The current British HIV Association (BHIVA) treatment guidelines make the following recommendations for changing from a first-line therapy:

• Treatment should be considered to have failed to control HIV only if there have been two viral load tests at least two weeks apart which both show that viral load is above 50 copies/ml.

• Only consider virological failure after assessment of adherence, intolerability, drug interactions and/absorption and incorrect dosing.

• Testing for resistance is recommended, on both current and stored pre-treatment samples if possible.

• If viral load is too low to have a resistance test, the replacement treatment should involve a completely new set of drugs.

• If no resistance is found, augmenting or intensifying the regimen is an option.

• If likelihood of resistance is high, consider changing all drugs.

• If changes are being considered because of toxicity, changing a single agent is acceptable if viral load is below 50 copies/ml.

• If there have been problems with adherence, the failing treatment should be replaced with drugs which are easy to take, and support with adherence should be provided.

• If viral load is above 50 copies/ml during the first 24 weeks of treatment, but has previously been below 50 copies/ml, the recommended action is to change all drugs.

• Some doctors may consider delaying a switch in treatment if viral load rebounds to a low level, such as between 500 and 1000 copies/ml. This is because tests for drug resistance, which may help pinpoint which drugs are unlikely to be effective in the replacement treatment, are more reliable at viral loads above 1000 copies/ml. Choosing to delay may increase the risk of further drug resistance developing. Because of this risk, people whose viral load has rebounded above 1000 copies may be better off stopping their treatment while waiting for the results of their drug resistance test.

• The timing of a switch in therapy will be influenced by the drug options available. If a second combination seems very likely to reduce your viral load to undetectable levels, then an earlier switch will offer the least possible risk of resistance developing. If you have fewer drug options available, you may be more inclined to switch later.

• The causes of treatment failure may be complex, and there is no clear evidence to guide the choice of replacement drugs, though drug resistance testing may be helpful in the short term.

The following recommendations for second-line highly active antiretroviral therapy (HAART) guidelines are made:

• Replace two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (PI) with two new and active NRTIs, guided by resistance testing if possible, and one non-nucleoside reverse transcriptase inhibitor (NNRTI) and / or a boosted PI.

• Replace two NRTIs and one NNRTI with two new NRTIs and a boosted PI.

• Replace three NRTIs with two new and active NRTIs, guided by resistance testing if possible, and one NNRTI and / or a boosted PI.

Switching from nucleoside reverse transcriptase inhibitor-based treatment

The use of triple nucleoside reverse transcriptase inhibitor (NRTI) regimens as first-line therapy is no longer recommended due to several large-scale trials to showing triple NRTIs to be inferior to two NRTIs and an NNRTI or PI.

If you are currently on a triple NRTI regimen, you should change if you have not achieved a viral load below 50 copies/ml for more than six months or if you have become undetectable but have previously taken single or dual NRTI therapy.

There is too little clinical data to make definite choices regarding the next therapy choices. Theoretically, both NNRTIs and PIs should remain available for use.

Where NRTIs have been used as the backbone of the first regimen, data on resistance patterns have the following implications for sequencing:

• Where a 3TC-containing regimen is used as first-line treatment, it is highly likely that 3TC resistance will emerge if the regimen fails. Resistance to d4T or AZT is far less likely to emerge, and one study suggests no loss of sensitivity to these drugs in people without genotypic resistance, suggesting that these drugs can be used again later (Maggiolo 2002).

• ddI (didanosine, Videx / VidexEC) can be used after the development of resistance to 3TC, and is not seriously affected by the development of thymidine analogue mutations (TAMs).

• Abacavir can probably be used after the development of resistance to 3TC, providing that fewer than four TAMs are present. If the failure of a tenofovir (Viread)-based regimen has resulted in the development of the K65R mutation, abacavir may not be effective.

• Tenofovir can be used in the presence of NRTI resistance associated with AZT or d4T, although larger numbers of mutations reduce the likelihood it will be effective. 3TC resistance alongside thymidine analogue mutations improves the chances of success.

• d4T after AZT, or AZT after d4T, may be less effective if TAMs have developed.

See Resistance to nucleoside and nucleotide reverse transcriptase inhibitors in Anti-HIV therapy: Resistance for further information.

Sequencing of regimens

Most people in the United Kingdom will start treatment with an NNRTI, so their second regimen is likely to comprise a boosted protease inhibitor plus two nucleoside analogues if the reason for switching treatment is virologic rebound rather than adverse events such as lipodystrophy.

The protease inhibitors most likely to be used in second-line therapy are:

• Kaletra (lopinavir/ritonavir), the most frequently prescribed protease inhibitor.

• Atazanavir, boosted with ritonavir; once daily, may allow sequencing of other protease inhibitors afterwards because of a unique resistance profile that may not lead to cross-resistance with other PIs.

• Saquinavir, boosted with ritonavir, twice daily.

Ritonavir-boosted indinavir is less likely to be recommended because several studies show that it is less well tolerated than ritonavir-boosted saquinavir.

Nelfinavir is highly unlikely to be recommended because the drug has been shown inferior to Kaletra in treatment-naive patients.

References

Badaro R et al. Efficacy and dafety of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) versus lopinavir/ritonavir (LPV/RTV) in combination with tenofovir (TFV) and one NRTI in patients who have experienced virologic failure to multiple HAART regimens: 16-week results from BMS AI424-045. Antivir Ther 8: S212, 2003.

Hammer S et al. A randomized, placebo-controlled trial of saquinavir (SQV)sgc, indinavir (IDV) or nelfinavir (NFV) in combination with amprenavir (APV), abacavir (ABC), efavirenz (EFV) & adefovir (ADV) in patients (Pts) with protease inhibitor (PI) failure. Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract LB7, 2001.

Hellinger J et al. (SQV) and lopinavir / ritonavir (LPV/R) twice daily in protease inhibitor (PI) naive hiv+ individuals: protease inhibitor concentrations and week 24 results. Antivir Ther 8: S339, 2003.

Maggiolo F et al. Thymidine-associated mutations selection during first HAART. Sixth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P232, 2002.

Phillips AN. Impact of previous ZDV and ddI/3TC nucleoside switches on virologic outcome in 1290 people on HAART. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, France. abstract 573, 2003.

Yazdanpanah Y et al. Clinical efficacy of antiretroviral combination therapy based on protease inhibitors and non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials. British Medical Journal 328: 249-253, 2004.