Cautious optimism for new class of anti-HIV drugs

Exciting new data from a brand new class of anti-HIV drugs called integrase inhibitors were presented last month in Denver at the Thirteenth Conference on Retroviruses and Opportunistic Infections (CROI). Although there were reports from two integrase inhibitors, Merck's drug, code-named MK-0518, is the furthest along in development, and appears to pack the most potent punch ever seen against HIV that is resistant to most available anti-HIV drugs.

At the moment, the most potent 'salvage' regimen available is the combination of ritonavir-boosted tipranavir (Aptivus) with T-20 (enfuvirtide, Fuzeon) used with what is known as an 'optimised background regimen' – new and recycled anti-HIV drugs that might still have some effect against HIV, based on the results of resistance testing. Although this combination is helping many highly treatment-experienced individuals stay well, there are some trade-offs: notably, self-injection of T-20 twice daily and the possibility of increased blood fats and liver problems associated with ritonavir and tipranavir, respectively.

Although the MK-0518 data are very preliminary, they compare favourably with the tipranavir/T-20 combo. After 16 weeks on this drug with an 'optimised background regimen', at least 70% of highly treatment-experienced study participants -98% of whom were resistant to all protease inbitors- achieved a viral load below 400 copies/ml. Since MK-0518 caused no more side-effects than the participants on an inactive placebo – at least, in the short-term – and it appears not to interact with other anti-HIV drugs, this is a major advance over currently-available therapies. However, MK-0518 is only available in clinical trials: details of UK sites will be announced on aidsmap.com if, and when, phase III studies begin here.

A second integrase inhibitor from Gilead Sciences – code-named GS 9137 – also appears to be very potent in both treatment-naive and treatment-experienced individuals, according to data from a short-term study presented in Denver. However, this drug needs to be boosted with ritonavir, and is also expected to have some interactions with other anti-HIV drugs.

Studies confirm AZT fat loss link, with no easy or fast recovery

Two different studies provide more evidence that AZT (Retrovir, and also in Combivir and Trizivir) is associated with fat loss, or lipoatrophy. One study examined limb fat in two groups of people new to anti-HIV therapy both taking efavirenz (Sustiva). After a year, the group that also took tenofovir and FTC (Truvada) had significantly more limb fat than those who also took AZT and 3TC (Combivir).

Another study found that people who switched from AZT-containing anti-HIV regimens to regimens containing either tenofovir (Viread) or abacavir (Ziagen) were significantly less likely to recover limb fat after a year compared with those who switched from d4T (stavudine, Zerit).

d4T was the first drug to be associated with fat loss. The latest studies suggest that whilst AZT may take longer to cause fat loss than d4T, regaining some of this lost fat after stopping the drug may also take longer.

Switching early from AZT or d4T (or never taking them in the first place) appears to be the best way to avoid fat loss, even though a variety of treatments are being investigated to treat this side-effect.

The most promising so far is the anti-diabetes drug, pioglitazone (Actos), which was reported in Denver to increase limb fat by about 400g after a year in people with lipoatrophy who were not taking d4T at the same time. However, since they started with an average of 2.9kg, and the amount of limb fat in the general population is around 8kg, no-one on the drug actually noticed the difference.

PIs, not NNRTIs, increase heart attack risk

The 16% per year increased heart attack risk seen in people taking anti-HIV therapy is caused by protease inhibitors (PIs) and not non-nucleoside reverse transcriptase inhibitors (NNRTIs), according to the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study presented in Denver at the Conference on Retroviruses and Opportunistic Infections. The study showed that this increased risk was partially due to the changes in blood fat levels caused by protease inhibitors.

Fortunately two small and short-term studies are suggesting more effective ways to treat high blood fat levels. The first found that people with high levels of blood fats known as triglycerides but low levels of another kind of blood fats (LDL or ‘bad’ cholesterol) may benefit from a combination of fish oil supplements and the fat-lowering drug fenofibrate (Fenogal/Lipantil/Supralip 160) if they have failed to respond to either treatment alone. The second found that adding the cholesterol absorption inhibitor, ezetimibe (Ezetrol), to the fat-lowering drug pravastatin (Lipostat) can safely and effectively reduce levels of both total and LDL cholesterol.

One pill once daily by end of year?

Gilead Sciences and Bristol Myers Squibb (BMS) announced in January that they now have data showing that a fixed dose combination pill combining Gilead’s Truvada (tenofovir and FTC [emtricitabine]) with BMS’s efavirenz (Sustiva) provides the same amount of medicine in the blood to fight HIV as the separate components. This once-daily single pill may help people new to anti-HIV therapy adhere better to therapy. The announcement came as a surprise, since the companies had previously announced that they were experiencing difficulties in getting the formulation right. They will be applying for formal US regulatory approval by the middle of 2006; applications for European approval usually lag behind by several months. If approved, the new formulation will be the first once-daily HIV treatment comprising drugs from two classes of antiretrovirals.

Another CCR5 inhibitor study terminated

One of several trials of Pfizer’s investigational CCR5 inhibitor has been stopped early by the independent Data Safety Monitoring Board (DSMB). A study comparing once-daily maraviroc with efavirenz (Sustiva) in over 200 people who had never taken HIV therapy before found that after 16 weeks of treatment, once-daily maraviroc did not prove itself to be “non-inferior” to efavirenz.

However, a study comparing twice-daily maraviroc against efavirenz will continue, as will studies examining once- and twice-daily maraviroc involving individuals with previous experience of HIV treatment. All the studies combine maraviroc with Combivir (AZT/3TC).