With the recent approval of a fourth class of drugs - fusion inhibitors - and several second generation protease inhibitors, treatment options for people with lengthy experience of anti-HIV drugs - called salvage therapy - are both myriad and increasingly complex.

The most useful definition of salvage therapy is one which describes antirteroviral therapy used in people who have experience - and resistance - of the main classes of drugs used until 2003: NRTIs, NNRTIs and PIs. With the availability of the fusion inhibitor Fuzeon (T-20, enfuvirtide) it is now possible for some people with HIV to harbour virus that is resistant to all four classes of drugs.

Before choosing a salvage regimen, you and your doctor should consider and investigate the reasons previous treatments failed. Some factors, such as drug resistance and low blood concentrations of particular drugs, may influence your approach to salvage therapy. For example, resistance testing can identify which drugs are most likely to be effective for you.

Also see Options when treatment is failing in Anti-HIV therapy: Changing treatment and Resistance testing to select treatment in Anti-HIV therapy: Resistance.

Effectiveness of salvage therapy

Until recently, it was found that people who have experienced treatment failure across the three main classes of antiretrovirals have a relatively poor chance of achieving an undetectable viral load with salvage therapy. For example, a 2000 study found that the more previous regimens a person has taken, the less likely they were to achieve undetectable HIV. Here, 60% of patients had a viral load below 50 copies/ml after one year on their third regimen while only 36% sustained undetectable viral load on their fourth regimen, and no-one on their fifth or sixth regimen had undetectable viral load. In this small study of 32 men, the number of resistance mutations at baseline was the only predictor of response (Fessel).

With the availability of T-20 (enfuvirtide, Fuzeon), tipranavir (Aptivus) and TMC-114 it is now possible for a larger minority of highly antiretroviral-experienced people to achieve an undetectable viral load.

However, it is very important that these drugs are not added one by one to a failing regimen. A number of recent studies have highlighted some basic rules for successful salvage therapy:

• Switch to a new salvage PI before too many primary protease inhibitor mutations have accumulated. Having more than two primary PI mutations is strongly correlated with a reduced risk of response to both tipranavir and TMC-114.

• Use resistance testing and treatment history to select a background regimen that contains as many active agents as possible. Success is strongly correlated with the number of active agents in the background regimen.

• Use either tipranavir or TMC-114 in combination with T-20 for the greatest antiviral effect.

• Salvage regimens that do not include T-20 may need to use up to six or seven drugs to achieve viral suppression. This strategy is called mega-HAART.

Characteristics of successful salvage regimens

The latest BHIVA guidelines discuss in detail the best ways to achieve the most lasting and suppressive salvage regimen.

• If the person with HIV is naive to a class of drug - e.g. fusion inhibitor - it is particularly important to provide this agent whenever possible to optimise therapy. This can be used with an optimised background therapy, including new or recycled drugs from other classes and/or unlicensed or experimental options.

• Improved outcome is more likely with the use of drugs within classes to which the person with HIV has not been exposed and to which resistance is unlikely or absent.

• Starting salvage therapy at a lower level of detectable viral load (between 5000 and 10,000 copies/ml) appears to be more successful to achieving undetectable levels, since there would less chance for more resistant mutations to appear at this level, the virus may be less fit, and even a suboptimal salvage regimen may be enough to suppress virus at this low level.

• Resistance testing and therapeutic drug monitoring is strongly recommended in all cases where there are difficult choices to make.

See Resistance testing to select treatment in Anti-HIV therapy: Resistance and Anti-HIV therapy: Testing drug levels

Researchers are increasingly focusing on the relationship between drug resistance and drug levels as a predictor of the likely success of salvage therapy. This issue is discussed in more detail in C_min and antiviral activity in Anti-HIV therapy: Testing drug levels.

Ritonavir-boosted tipranavir

Tipranavir is a new protease inhibitor that is boosted with ritonavir. The drug appears to be more effective than previously licensed protease inhibitors in suppressing drug-resistant virus.

Tipranavir has been studied in two large international trials, RESIST 1 and 2, both of which showed that approximately one quarter of patients with multiple protease inhibitor experience achieved viral load below 50 copies/ml after 24 weeks if they received tipranavir, compared to approximately ten per cent of those who received another protease inhibitor chosen after resistance testing.

See Tipranavir in Drugs used by people with HIV for further information.

Ritonavir-boosted TMC114

TMC-114 is an experimental protease inhibitor which may be licensed in 2006. It is boosted with ritonavir.

TMC-114 has proved highly effective in patients with multiple protease inhibitor experience. In the POWER study approximately half of those who received TMC-114 achieved viral load below 50 copies, a significantly greater proportion than in the group that received another protease inhibitor chosen by resistance testing.

For further information, see TMC114 in Drugs used by people with HIV: Protease inhibitors.

T-20

T-20 is a fusion inhibitor, a new class of drug that is not cross-resistant to any existing drug classes. It is therefore a very important drug in salvage therapy, since the addition of a drug from a new class has been shown repeatedly to result in a better outcome.

The disadvantage of T-20 is that it must be injected twice daily, which some patients find difficult.

For further information see T-20 - overview in Drugs used by people with HIV.

T-20 plus new protease inhibitors

Several recent studies have shown that the use of T-20 with a protease inhibitor to which an individual is naive, together with a background regimen of drugs that have been chosen as a result of resistance testing and careful analysis of an individual's treatment history, results in a better response than the addition of either agent alone.

These drugs are:

• Ritonavir-boosted lopinavir (Kaletra).

• Ritonavir-boosted tipranavir (Aptivus).

Kaletra

For TORO-1 and TORO-2 participants who received Kaletra and two other active agents in their background regimen, inclusion of T-20 in the regimen resulted in significantly better outcomes. 52% of the T-20 group had viral load below 400 copies/ml at week 48, compared to 27% of the optimised background group (Miralles 2004).

Tipranavir

An analysis of participants in the RESIST 1 and 2 studies showed that 70% of the patients who took tipranavir / ritonavir and were previously naﶥ to T-20 achieved a viral load reduction of at least 1log after 24 weeks of treatment. However, only 31% of T-20-experienced patients achieved this outcome (Valdez 2005).

Dual protease inhibitor boosting

A number of clinicians are now double boosting PIs, using ritonavir to increase blood levels of two other PIs, for example by combining Kaletra and amprenavir or saquinavir, particularly in second-line and later regimens. Kaletra has been combined with amprenavir but this combination produced an unexpected decline in amprenavir and lopinavir levels (Duval 2002; Peytavin 2001). This points to the difficulty in predicting drug interactions when several PIs and NNRTIs are combined. Some drugs, such as efavirenz, will speed-up clearance of the boosted PI, reducing some of the beneficial impact of ritonavir (Aarnoutse 2002). Although the ritonavir dose may be increased to offset this, the potential for ritonavir-related toxicities then increases.

Utilising low dose ritonavir to boost both lopinavir and saquinavir - with no other antiretrovirals - was the subject of two studies, one from the United States in people who were naive to PIs and one from Germany as a salvage regimen in the heavily PI-pretreated.

The United States double boosting data was based on the first 48 weeks of a 72 week open label pilot study that combined soft gel saquinavir (Fortovase, 1000mg) and Kaletra (400/100 mg) twice daily in 20 PI-naive patients with moderate HIV disease. The combination appeared to be effective, in that 70% of patients achieved viral loads of less than 400 copies/ml, and 65% reached 50 copies/ml and the mean increase in CD4 cell counts was 194 cells/mm³.

Sharp increases in total cholesterol were seen in 13 of the 14 remaining on therapy warranting protocol-mandated lipid-lowering therapy. However, the most disconcerting side-effect was the amount (on average 3.9 kg) and extent (two thirds of the cohort) of weight gain seen. At baseline, 7% each of study entrants had either abdominal fat gain or buffalo hump, compared with 53% and 33% at 48 weeks. There was only one new case of mild or moderate fat loss, however. The fat gain confounded the researchers, who theorised that higher than usual peak levels of either saquinavir or lopinavir or both could have caused the fat gain. Interestingly, only trough levels were reported, and were found to be similar to those seen in single boosted studies (Hellinger 2003)

The German study looked at the same doses of saquinavir and Kaletra in 121 heavily pre-treated patients from the Frankfurt HIV Cohort who were experiencing treatment failure due to either resistance (58%), toxicity (39%) or both (3%). Twenty-four week results were available for 64, of which 52 (81%) were still on therapy.

The focus of this presentation was to tease out the factors that led to a response to treatment, which was defined in one of four ways. If baseline viral load was below 400 copies/ml then response was defined as it remaining below 400 copies/ml at 24 weeks. If baseline viral load was between 400 and 1000 copies/ml at baseline, it should remain below 1000 copies/ml at 24 weeks. If baseline viral load was between 1000 and 100,000 copies/ml, it should reach below 5000 copies/ml at 24 weeks. If baseline viral load was above 100,000 copies/ml, it should reach a level below 10,000 copies/ml at week 24.

Forty-five of the 52 (86%) were classed as responders. Responders were found to have a higher CD4 cell count (196 vs. 66 cells/mm³) and had fewer resistance mutations at baseline (2 vs. 8). Although plasma concentration levels of both saquinavir and lopinavir were lower in non-responders compared with responders, this did not reach statistical significance (Staszewski 2003).

Double boosting may work by multiple mechanisms when atazanavir is combined with saquinavir. Whilst ritonavir boosts saquinavir trough and peak levels through inhibition of the cytochrome P450 enzyme in the gut and liver, atazanavir slows the rate at which saquinavir is eliminated from the body, extending the drug's half-life (Boffito 2004a).

The ATSAQ study gave saquinavir, atazanavir and ritonavir at doses of 1000, 300 and 100mg respectively as the sole HIV therapy to 40 patients who were protease-inhibitor experienced (though not atazanavir-experienced) and failing on their current regimen. They had taken an average of three previous protease inhibitors and eight previous regimens.

After a median follow-up of 32 weeks, 85% of patients had a viral load under 400 copies/ml on an intent-to-treat analysis, and 60% (24 patients) below 50 copies/ml. Three patients discontinued, two due to atazanavir-related jaundice, and one due to virological failure. Ninety-three per cent of those remaining on treatment achieved viral loads under 400 copies/ml. The baseline viral load influenced patients results. The median viral load at 32 weeks with those with a baseline under 100,000 copies/ml was less than 50 copies/ml by week 12. In patients starting at over 100,000 copies/ml, median viral load was 800 copies/ml at week 12 and 90 copies/ml by week 24 (Rottman 2004).

A preliminary study by Charles Farthing of the AIDS Healthcare Foundation found that atazanavir and fosamprenavir might have a mildly synergistic effect, regardless of ritonavir boosting. However a pharmacokinetic study in HIV-positive individuals showed no synergistic effect and even a modest reduction in saquinavir levels that could be compensated for by increasing the ritonavir dose to 200mg a day (Boffito 2004b). A case study of two patients by Clifford Leen of Western General Hospital, Edinburgh found that it might be possible to combine tipranavir and indinavir without the decrease in drug levels seen when tipranavir is combined with other PIs.

Dual protease inhibitors without ritonavir boosting

An alternative strategy to boosting with ritonavir is the use of two PIs (excluding ritonavir), known sometimes as dual PI therapy. Although atazanavir combined with saquinavir looks promising for those concerned about lipid profiles, and for those who are intolerant to ritonavir, the study from Haas and colleagues that compared atazanavir and saquinavir with ritonavir-boosted saquinavir was not large enough to detect a difference in efficacy between the two doses of atazanavir and ritonavir with saquinavir. In fact, the 045 study suggests that atazanavir boosted with ritonavir is more effective than atazanavir and saquinavir, since resistance to atazanavir is likely in previously PI-treated patients (Badaro 2003). Balancing tolerability, side-effects and effectiveness continues to be a major sticking point in all HAART regimens, as noted in the latest BHIVA guidelines.

The LOPSAQ study is a cohort analysis of 64 highly treatment-experienced patients who have received treatment with Kaletra and saquinavir. No NRTI backbone was taken and patients had received an average of nine prior drugs, including three protease inhibitors. By week 24, 70% of patients had a successful response (Staszewski 2003).

Prior double PI studies have shown mixed results. The ACTG 398 study randomised individuals to receive amprenavir, efavirenz and adefovir (Preveon) plus either nelfinavir, indinavir, saquinavir or placebo. NNRTI-naive patients responded better in this study, but those who received two PIs also did better in this study, regardless of which PIs they had taken previously (Hammer 2001). The effectiveness of nelfinavir with saquinavir after prior PIs was unsuccessful among people with high viral load (median 187,000 copies/ml; Reiser). When combined with d4T, nelfinavir and saquinavir had a transient benefit among people who had previously failed on ritonavir-boosted indinavir/ritonavir (Rockstroh).

Waiting for more options

If you have detectable viral load and few immediate options for salvage treatment, continuing with existing treatment may have its advantages, not least because remaining on therapy - even failing therapy - has clinical benefits.

Adding one drug to a failing combination is generally seen as very poor medicine. If a person has very few options among currently available drugs, they may, depending on their health, decide to wait until they have two or three new drugs available to them before switching to a different combination.

2002 data from the EuroSIDA cohort suggests that deciding whether to remain on a failing combination in these circumstances may be influenced by the CD4 count. The findings also suggest that mega-HAART regimens may be warranted in this group of patients.

Amongst 1106 people with CD4 cell counts below 50 cells/mm³, disease progression was reduced by 50% in those receiving HAART (despite viral rebound) compared to those on no therapy.

The overall rate of clinical disease progression or death decreased with each additional drug received in the preceding three months; rates did not change with total number of drugs ever taken. The rate of progression or death rose with increasing latest viral load measurement, and decreasing latest CD4 cell count, haemoglobin and body mass index (BMI). PCP prophylaxis resulted in a lower rate of new AIDS-defining illness or death, whereas MAC prophylaxis increased the rate slightly.

After adjusting for all other variables, there was striking effect on clinical progression and death caused by the number of antiretrovirals taken in the previous three months. Receiving a regimen of five or more drugs reduced the rate the most (82% reduction in risk), and the risk of progression or death increased the fewer drugs taken, with a fivefold greater risk for those on no antiretrovirals. A lower CD4 cell count and a lower haemoglobin level was also found to be significant for both disease progression and death, whereas a 1 log₁₀ rise in viral load and a reduction in BMI was only associated with clinical progression, not illness or death. No significance was found for the class of drug taken, total time on therapy, or time on therapy with viral load above 500 copies/ml. (Miller 1998)

See Options when treatment is failing in Anti-HIV therapy: Changing therapy for further discussion of this strategy.

Mega-highly active antiretroviral therapy

Although mega-HAART (also known as giga-HAART or multiple-drug rescue therapy [MDRT]) is controversial, since it often involves more than double the usual antiretrovirals used in HAART and requires a huge amount of motivation from those on it due to adherence and side-effect issues, a study from Vancouver provides evidence that until something better comes along, mega-HAART means survival, at least in the short-term.

Investigators at the BC Centre For Excellence at St. Paul's Hospital in downtown Vancouver, BC, compared 341 HAART-experienced patients who began mega-HAART between August 1997 and 31 July 2000 with 1047 HAART-naive patients who began their first HAART therapy during the same period, and followed them for an average of three years.

The HAART-experienced patients had been on at least two prior triple HAART regimens and had had two consecutive viral load rebounds above 400 copies/ml after previously achieving an undetectable viral load. They had taken an average of seven different antiretrovirals prior to mega-HAART, and 36% of them had taken drugs from (and were resistant to) all three classes. The mega-HAART therapy was chosen based on individual patient history and preference, as well genotype resistance testing, and consisted of an average of six antiretrovirals from all three classes. Hydroxycarbamide was also used in two-thirds of cases.

The study found that although whilst on therapy the patients on mega-HAART had, on average, lower CD4 counts (230 vs. 390 cells/mm3) and slightly higher viral loads (112 vs. 104 copies/mL) the death rate was not statistically different after three years (14.2% vs 10.9%; p = 0.105). Put another way, those patients on mega-HAART had only a slightly higher relative risk (1.17) of dying over three years than those on their first HAART regimen.

This is likely explained by the fact that mega-HAART was able to keep viral load suppressed and CD4 counts up above 200 cells/mm3, the threshold of severe immune suppression. The authors found that adherence was good, there was no unexpected toxicity and the overall dropout rate was low.

Although this is by no means an ideal solution to the increasing amounts of people with multidrug resistant virus and few treatment options left, the authors conclude that judicious use of this strategy may serve as the necessary bridging mechanism that will allow selected patients to eventually benefit from more attractive therapeutic options as they emerge. (Lee)

Some mega-HAART studies appear to have produced better responses than others, and it's unclear why this is so. Possible contributing factors include the extent of prior antiretroviral exposure, interrupting treatment prior to mega-HAART, and the availability of support when treatment begins.

There is conflicting research over what exactly best determines a person's response to mega-HAART, and that a treatment interruption before switching may enhance viral sensitivity to the multidrug combination.

See Treatment interruption before salvage therapy in Anti-HIV therapy: Structured treatment interruption for a more detailed discussion.

It is possible that certain drugs may impair viral fitness in such a way that any virus produced is less harmful to the immune system or less able to infect cells.

The M184V mutation associated with abacavir and 3TC treatment appears to be important in this respect, reducing the number of mistakes that HIV makes when copying itself. Mutants which have already emerged in response to drug pressure may be preserved by continuing pressure from 3TC or abacavir, speculate some experts.

See Viral fitness, drug resistance and the immune system in Anti-HIV therapy: Restoring the immune system.

Preliminary research suggests that resistance patterns may determine a person's response to mega-HAART, and that a drug holiday before switching may enhance viral sensitivity to the multidrug combination.

The Frankfurt team investigated resistance patterns amongst people who commenced mega-HAART, and found that non-responders had cross-resistance to three or four PIs, and were sensitive to less than four of the drugs in the mega-HAART combination. Drug holidays of three to four months before commencing mega-HAART led to a return to wild-type virus and a greater chance of a successful response to therapy (Miller V; Katlama). In the French GIGHAART study, nearly two-thirds of participants who took a drug holiday before starting mega-HAART had a one log reduction in viral load compared with a quarter of participants who moved directly from a failing combination to mega-HAART (Katlama). However, it is not known whether the treatment interruption will provide a clinical benefit in the longer term.

It is possible that certain drugs may impair viral fitness in such a way that any virus produced is less harmful to the immune system or less able to infect cells. The M184V mutation associated with abacavir and 3TC treatment appears to be important in this respect, reducing the number of mistakes that HIV makes when copying itself. Mutants which have already emerged in response to drug pressure may be preserved by continuing pressure from 3TC or abacavir, speculate some experts. See Viral fitness, drug resistance and the immune system in Anti-HIV therapy: Restoring the immune system

Another possibility is that preservation of the M184V mutation by ongoing 3TC or abacavir treatment will enhance the anti-viral effect of adefovir. This drug is more active against HIV which carries the M184V mutation than against wild-type virus, and a recent salvage study of adefovir and efavirenz, with or without background abacavir or 3TC treatment, showed that ongoing abacavir or 3TC treatment was a significant predictor of achieving viral load below 500 copies after commencing efavirenz/adefovir (Shulman).

The nucleotide analogue reverse transcriptase inhibitor adefovir was used in some mega-HAART and salvage therapy studies due to its strong antiviral effect against virus with the 184 resistance mutation (Miller M 1999). However, adefovir failed as an anti-HIV agent during the development process due to excessive toxicities. A similar drug called tenofovir has since been approved for use in many parts of the world. Like adefovir, tenofovir has improved antiviral effect against virus with the 184 mutation. It is also active against HIV with the Q151M mutation (associated with multi-NRTI resistance), but shows reduced susceptibility to the T69S insertion mutations (Miller M 2001).

Key salvage studies

See also Choosing a second-line regimen in Anti-HIV therapy: Changing treatment.

Manfredi evaluated 35 people treated with efavirenz-containing salvage therapy following failure of second-line HAART. Regimens also contained a new protease inhibitor while nearly half changed at least one NRTI. After 9-22 months follow-up, only one-third had a sustained drop in viral load. 4/35 had undetectable viral load at six months but none sustained this at 12 months. A significant rise in CD4 levels was sustained during follow-up.

Becker presented Abbott M98-957. In this study 57 individuals with a median baseline viral load of 31,000 copies/ml who had failed on at least two protease inhibitors received lopinavir/r and efavirenz plus 2 NRTIs. All patients were NNRTI-naive. After 24 weeks 75% had viral load below 400 copies. Phenotypic resistance testing at baseline showed that 68% of participants had greater than fourfold reduced sensitivity to at least three protease inhibitors, and the mean reduction in sensitivity was 16-fold. Patients were also randomised to either 400/100 mg or 533/133 mg lopinavir/r; virological performance in the 533/133 mg arm showed a trend to superiority (p=0.417). Median CD4 increase at week 24 was +37; 40% of participants experienced increases in cholesterol above 300 mg/dL (7.7 mmol/L) or triglycerides above 750 mg/dL (19.2 mmol/L).

Masur presented CNA2007 which tested amprenavir, abacavir plus efavirenz in 101 people with lengthy treatment histories. Sixty percent of participants had received two PIs in the past, 72% had received 4-5 nucleoside analogues, and 44% had taken an NNRTI as well. After 48 weeks, the best response was seen in those who started the new combination with a viral load below 40,000 copies and/or had no prior NNRTI experience. Intent-to-treat data showed that 20 of 60 NNRTI-naive participants had viral loads below 400 after 48 weeks. Among those with previous use of an NNRTI, only three of 41 people had viral loads below 400. Cross-resistance between efavirenz and other NNRTIs is assumed to be the cause of the poorer responses seen in people with NNRTI experience. In addition, it is now known that efavirenz halves the drug levels of amprenavir when the two drugs are taken together. Recent drug interaction studies have found that the addition of ritonavir or nelfinavir to the amprenavir/efavirenz combination restores amprenavir to safe and effective levels.

Hammer conducted a salvage study of amprenavir/efavirenz /abacavir/adefovir with or without an extra protease inhibitor also produced poor results. Nearly 60% of participants withdrew due to drug toxicity or viral rebound. Intent-to-treat analysis showed that 35-39% of people on dual PI regimen had viral loads below 200 after 24 weeks, compared with 28% in the placebo arm. Previous experience of NNRTI significantly influenced response; 43% of NNRTI individuals were below 200 compared with 16% of the NNRTI-naive.

Hammer reported final results of ACTG 398. 481 participants were selectively randomised taking into account prior PI exposure to soft gel saquinavir 1600 mg twice daily (n=116), indinavir 1200 mg twice daily (n=69), nelfinavir 1250 mg twice daily (n=139) or placebo matched for active PIs twice a day (n=157) in combination with open-label amprenavir 1200 mg twice daily, abacavir 300 mg twice daily, efavirenz 600 mg once daily, and adefovir dipivoxil 60 mg once daily (with L-carnitine supplementation 500 mg once daily). Overall, a higher proportion of NNRTI-naive to NNRTI-experienced patients achieved HIV-1 RNA below 200 copies/ml (43% vs 16%, respectively). Baseline sensitivity to efavirenz was associated with suppression of HIV-1 RNA at 24 weeks to below 200 copies/ml; conversely more than 10-fold reduction in efavirenz susceptibility was associated with less likelihood of effective suppression. Of 481 patients, 148 (31%) had HIV-1 RNA below 200 copies/ml at week 24. 201 (42%) discontinued study treatment: 58 (29%) for virologic failure, 143 (71%) for other reasons including toxicity. In the saquinavir, indinavir, nelfinavir, and placebo arms, the proportions of patients with HIV-1 RNA below 200 copies/ml were 34% (40/116), 36% (25/69), 34% (47/139) and 23% (36/157), respectively. After preliminary analysis at 48 weeks, the proportions were 34%, 33%, 26% and 22%, respectively. Overall, at 48 weeks, a higher proportion in the combined dual PI arms had HIV-1 RNA below 200 copies/ml than placebo (30% vs 22%: P=.04). The study was not designed to compare dual PI arms with each other.

Moreno tested a salvage regimen of ritonavir/indinavir and an NNRTI. It proved moderately effective in heavily pre-treated patients but almost 60% reported drug-related adverse events. Thirty-four individuals receiving ritonavir/indinavir plus either nevirapine (n=8) or efavirenz (n=26) were analysed for viral load responses, drug levels and resistance. Twenty-four had already failed nevirapine therapy, and the group was heavily PI-experienced, with an average exposure of 3.5 PIs prior to commencing the RTV/IDV regimen. More than half (62%) experienced a viral load decline of greater than 1 log at month 3, but response was poorer in those with the V82A or L90M mutations. Surprisingly, those with isolates resistant to ritonavir, indinavir and efavirenz had a better than average virological response, with a decrease of 1.35 log after three months, and 0.8 log at six months.

Wasmuth reported that efavirenz/abacavir had a modest effect in 40 treatment-experienced people who had taken at least three NRTIs and two PIs. 13 had previously used an NNRTI. The average viral load fell from 197,000 to 8,470 at week 4. However, by week 24, the average viral load had increased to approximately 23,000.

Khanna reported another abacavir/NNRTI study, this time in 23 heavily pre-treated but NNRTI and abacavir-naive individuals with a median viral load of 180,000 copies. Only 43% sustained a viral load reduction of more than 0.5 log at six months, and only two individuals achieved undetectable viral load at all. However, CD4 cell increases occurred in the absence of a virological response, and only 3 individuals experienced a significant CD4 cell reduction (greater than 30% reduction).

Albrecht conducted a study of individuals with extensive prior NRTI experience and found that either nelfinavir and efavirenz, or efavirenz alone, in combination with two NRTIs, were superior to nelfinavir plus two NRTIs (at least one NRTI was new for each participant). After 48 weeks 74% of those in the NFV/EFV arm and 60% of those in the EFV arm had viral load below 500 copies, compared with 35% of the NFV arm. These findings are somewhat surprising given the potency of protease inhibitors, and have yet to be fully explained.

A high level of cross-resistance among NNRTIs means that previous failure on one NNRTI makes benefit from other NNRTIs unlikely. However, a study conducted by Moyle in London found that key NNRTI resistance mutations, rather than previous use of an NNRTI, predicted response to salvage therapy containing an NNRTI.

Youle at the Royal Free Hospital in London used a backbone combination of ddI, hydroxyurea, efavirenz, two protease inhibitors (usually ritonavir and indinavir) and 3TC. Just over half of highly treatment-experienced patients enrolled in the study still had viral load below 50 copies/ml after more than two years on the regimen. Sixty patients with rising viral load were enrolled in the open label study, and had taken a median of two protease inhibitors before joining the study. However, 87% of participants were NNRTI-naive. The median duration of treatment experience prior to joining the study was 2.9 years (with one quarter having received at least five years of antiretroviral treatment by the beginning of 1998). Sixty per cent of patients had a previous AIDS diagnosis. Regimens were constructed around efavirenz (taken by all patients), ddI (taken by 73%), hydroxyurea (taken by 73%) and a protease inhibitor (mainly indinavir boosted with ritonavir). Drugs were not chosen on the basis of resistance testing because the study began in early 1998. The median number of drugs included in the regimen was five. After two years, 31 patients (52%) had viral load below 50 copies, and ten patients stopped therapy altogether. Five individuals died during the study, and a further nine developed an AIDS-defining illness (three cases of lymphoma, two cases of Kaposis sarcoma, once case each of PML, PCP, wasting syndrome and oesophageal candida). Of those on treatment, 72% had viral load below 50 copies after two years, and 72% had experienced CD4 cell increases (in two thirds of cases increases of more than 100 cells/mm3 were observed). The median number of drugs taken remained five after two years. Multivariate analysis showed that the only factors associated with a reduced chance of viral load below 50 copies and a CD4 cell increase were a higher baseline viral load, and previous NNRTI use.

Piketty tested a five-drug combination including ritonavir/saquinavir and efavirenz in 32 people who had not previously taken efavirenz nor saquinavir. Median baseline viral load was 4.3 log. Overall, on-treatment analysis shows 61% achieved undetectable viral load below 500 and 58% below 50 at week 48. Only 33% with high level phenotypic resistance to saquinavir at baseline achieved viral loads below 50 at week 48 in contrast to 79% of people with saquinavir-sensitive virus.

Montaner looked at the effectiveness of regimens of between five and nine drugs in two cohorts of people with extensive treatment experience (Cohort 1 n=106; Cohort 2 n=68). Regimens included up to four NRTIs, two PIs, 2 NNRTIs, with or without hydroxyurea. Cohort 1 took an average of five drugs, and Cohort 2 an average of 7. Median baseline viral load was 62,000 in Cohort 1 and 56,500 in Cohort 2. Average baseline CD4 count in both groups was around 200 cells. During weeks 58-68 of follow-up, 43% and 53% of Cohort 1 had viral load below 400 copies by intent-to-treat analysis and as treated analysis respectively. In Cohort 2, during weeks 25-35, these proportions are 46% and 54%.

Miller retrospectively studied the impact of mega-HAART in the Frankfurt Cohort. Six or more drugs were given to 50 people who had experienced multiple treatment failures. After 24 weeks of treatment, only 11 of 50 achieved viral loads below 500 . Multivariate analysis showed that high baseline viral load and extensive phenotypic resistance were associated with failure to suppress HIV to undetectable levels.

Grossman reported on mega-HAART regimens in 34 individuals with a mean of 9 drugs prior experience. All patients received abacavir, efavirenz and adefovir through expanded access programmes plus two protease inhibitors (commonly ritonavir/indinavir). Most also took additional nucleoside analogues, most commonly AZT/3TC or d4T/ddI. Hydroxyurea was used by some individuals. 68% achieved viral load below 40 copies on an ultrasensitive test on two occasions. Thirteen people (38%) had viral loads below 40 copies after six months of treatment. The regimens were well-tolerated. There was no difference in response between those who took a drug holiday prior to commencing mega-HAART, and those who did not, although numbers were small. Unexpectedly, individuals with prior NNRTI experience did better on an efavirenz-containing salvage regimen than those with no prior experience. They experienced greater viral load suppression (-3.86 log vs -2.22 log) and greater CD4 increases (+226 vs +209 cells), but it was unclear why this should be so.

References

Aarnoutse RE et al. The influence of efavirenz on the pharmacokinetics of a twice-daily combination of indinavir and low-dose ritonavir in healthy volunteers. Clin Pharmacol Ther 71: 57-67, 2002.

Albrecht M et al. Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. N Engl J Med 345: 398-407, 2001.

Barreiro P et al. Comparison of the efficacy, safety and predictive value of HIV genotyping using distinct ritonavir-boosted protease inhibitors. Int J Antimicrob Agents 20: 438-443, 2002.

Becker S et al. ABT-378/ritonavir and efavirenz: 24 week safety and efficacy data in multiple PI experienced patients. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, abstract 697, 2000.

Casado JL et al. A clinical study of the combination of 100 mg ritonavir plus 800 mg indinavir as salvage therapy: influence of increased plasma drug levels in the rate of response. HIV Clin Trials 1: 13-19, 2000.

Clotet B. New directions in protease inhibitor therapy. HIV Management: Sustaining Success Symposium. Fourth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P122, 1998.

Deeks S et al. Persistence of drug-resistant HIV-1 after a structured treatment interruption and its impact on treatment response. AIDS 17: 361-370, 2003.

Devereux H et al. Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy. AIDS 13: 123-127, 1999.

Duval X et al. Amprenavir inhibitory quotient and virological response in human immunodeficiency virus-infected patients on an amprenavir-containing salvage regimen without or with ritonavir. Antimicrob Agents Chemother 46: 570-574, 2002

Falloon J et al. HIV-1 genotype and phenotype correlate with virological response to abacavir, amprenavir and efavirenz in treatment-experienced patients. AIDS 16: 387-396, 2002.

Falloon J et al. Combination therapy with amprenavir, abacavir, and efavirenz in human immunodeficiency virus (HIV)-infected patients failing a protease-inhibitor regimen: pharmacokinetic drug interactions and antiviral activity. Clinical Infectious Diseases 30(2):313-318, 2002.

Fessel WJ et al. Salvage therapy and formulation of highly active antiretroviral therapy. Journal of AIDS 24(2):194-195, 2000.

Hammer S et al. Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. JAMA 288: 169-180, 2002.

Izopet J et al. Shift in HIV resistance genotype after treatment interruption and short-term antiviral effect following a new salvage regimen. AIDS 14: 2247-2255, 2000.

Katlama C et al. GIGHAART (ANRS 097): A prospective randomized trial comparing the efficacy of a salvage regimen administered with or without treatment interruption in patients with severe biological failure and extensive prior experience. Eighth Conference on Clinical Aspects and Treatment of HIV Infection, Athens, 28-31 October, abstract O16, 2001.

Kaufmann GR et al. Treatment response and durability of a double protease inhibitor therapy with saquinavir and ritonavir in an observational cohort of HIV-1-infected individuals. AIDS 12: 1625-1630, 1998.

Khanna N et al. Salvage therapy with abacavir plus a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor in heavily pre-treated HIV-1 infected patients. AIDS 14 (7):791-799, 2000.

Lalezari J et al. Enfuvirtide (T-20) in combination with an optimised background (OB) regimen vs OB alone: week 24 response among categories of treatment experience and baseline (BL) HIV antiretroviral (ARV) resistance. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, abstract H-1074, 2002.

Lyle LG et al. Effect of nelfinavir/indinavir/delavirdine in HIV+ patients with extensive antiviral experience. 12th World AIDS Conference, Geneva, abstract 12329, 1998.

Manfredi R et al. The use of efavirenz as a part of late rescue antiretroviral treatment. HIV Clinical Trials 2(5):413-420, 2001.

Mess T et al. Efficacy of salvage regimens after failure of first HAART. First International Conference on the Discovery and Clinical Development of Antiretroviral Therapies, St Thomas, abstract LB21A, 1998.

Miller V et al. Prognostic value of virus load levels in patients receiving HAART: the Frankfurt HIV cohort. Fourth Congress on Drug Therapy in HIV Infection, Glasgow, abstract OP6.12, 1998.

Miller V et al. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. AIDS 14(18):2857-2867, 2000.

Miller V et al. Association of virus load, CD4 cell count, and treatment with clinical progression in human immunodeficiency virus-infected patients with very low CD4 cell counts. Infectious Diseases 186(2): 189-197, 2002.

Miralles D et al. Virologic suppression of an active boosted PI regimen is significantly enhanced by the addition of a fusion inhibitor in treatment-experienced patients.42nd Annual Meeting of the Infectious Diseases Society of America, Boston, abstract 921, 2004.

Moyle G et al. Predictors of virological response to salvage regimens in treatment experienced patients. Antiviral Therapy 4(supplement 1):53, 1999.

Moreno S et al. Ritonavir/indinavir plus an NNRTI is effective after multiple failure: pharmacokinetic and resistance data. Antiviral Therapy 5, abstract 46, 2000.

Peytavin G et al. Amprenavir concentrations are dramatically decreased by association with ABT-378/r in HIV-infected patients. Second International Workshop on Pharmacology of HIV Therapy, Noordwijk, abstract 5.12, 2001.

Ruiz L et al. Virological and immunological benefit of a salvage therapy that includes Kaletra plus Fortovase preceded or not by antiretroviral therapy interruption in advanced HIV-infected patients (6 month follow-up). Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 421, 2002.

Shulman N et al. Efavirenz- and adefovir dipivoxil-based salvage therapy in highly treatment-experienced patients: clinical and genotypic predictors of virologic response. Journal of Acquired Immune Deficiency Syndromes 23(3):221-226, 2000.

Sonnenborg A et al. Clinical issues and assays. Fourth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract PL 3.3, 1998.

Soriano V et al. Monthly cyclic therapy as salvage intervention for heavily pretreated HIV-infected patients with virological failure. Second International Workshop on Salvage Therapy in HIV Infection, Toronto, abstract 14, 1999.

Stek M et al. European and South American Study of indinavir, efavirenz and ritonavir (EASIER). Fourteenth International AIDS Conference, Barcelona, abstract LpPp2208 2002.

Tran JQ et al. Delavirdine: clinical pharmacokinetics and drug interactions. Clinical Pharmacokinetics 40(3):207-226, 2001.

Valdez H et al. Tipranavir/ritonavir 500mg/200mg BID drives 24 week viral load below 400 copies/ml when combined with a second active drug (T-20) in protease inhibitor experienced HIV-positive patients. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract WeOa0205, 2005.

Veldkamp AI et al. The steady-state pharmacokinetics of efavirenz and nevirapine when used in combination in human immunodeficiency virus type 1-infected persons. Journal of Infectious Diseases 184(1):37-42, 2001.

Wasmuth J-C et al. Efficacy and safety of abacavir plus efavirenz as a salvage regimen in HIV-infected individuals after 48 weeks. AIDS 16(7):1077-1078, 2002.

Youle M et al. Brief report: two-year outcome of a multidrug regimen in patients who did not respond to a protease inhibitor regimen. Journal of Acquired Immune Deficiency Syndromes 29(1):58-61, 2002.

Grossman H et al. Mega-HAART: complex protective regimens for HAART failure. Second International Workshop on Salvage Therapy for HIV Infection, Toronto, abstract 23, 1999.

Lee N et al. Rates of Disease Progression among Human Immunodeficiency VirusInfected Persons Initiating Multiple-Drug Rescue Therapy. Journal of Infectious Diseases;188:137-141, 2003

Miller V et al. HIV drug susceptibility and treatment response to mega-HAART regimen in patients from the Frankfurt HIV cohort. Antiviral Therapy 5(1):49-55, 2000.

Montaner JSG et al. Multiple drug rescue therapy for HIV-infected individuals with prior virologic failure to multiple regimens. AIDS 15(1):61-69, 2001.

Piketty C et al. Phenotypic resistance to protease inhibitors in patients who fail on highly active antiretroviral therapy predicts the outcome at 48 weeks of a five-drug combination including ritonavir, saquinavir and efavirenz. AIDS 14(5): 626-8, 2002.

Rottman C et al. Atazanavir/ritonavir/saquinavir without any other antiretroviral drugs in protease inhibitor experienced patients with no reverse transcriptase inhibitor options: a 24 week cohort analysis. Seventh International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P21, 2004.

Youle M et al. Two year outcome of a multidrug regimen in patients who did not respond to a protease inhibitor regimen. Journal of Acquired Immune Deficiency Syndromes 29: 58-61, 2002.