Three- or four-drug combination therapy is now considered the standard of care for people with HIV. In most cases the foundation of combination therapy continues to be two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs or NtRTIs). Popular combinations include AZT (zidovudine, Retrovir) plus 3TC (lamivudine, Epivir), 3TC plus abacavir (Ziagen) and FTC (emtricitabine, Emtriva) plus tenofovir (Viread). These are available as the fixed-dose combinations Combivir, Kivexa and Truvada.

A three-drug NRTI backbone, such as AZT, 3TC and abacavir is used occasionally. This combination is available as the fixed-dose combination Trizivir. However, there is little evidence to indicate that this is more effective than a dual-drug NRTI or NtRTI backbone.

When choosing an NRTI or NtRTI backbone, several factors should be considered:

• Efficacy.

• Activity against HIV in the brain and central nervous system.

• Side-effects and toxicity profile.

• Resistance profile and likelihood of cross-resistance to other NRTIs.

• Dosing regimen.

The strengths and weaknesses of the different backbones are discussed at the end of this section. For further details of the effectiveness of the individual drugs, as well as dosing considerations and side-effects, see individual drug entries in Drugs used by people with HIV: Nucleoside reverse transcriptase inhibitors and Drugs used by people with HIV: Nucleotide reverse transcriptase inhibitors.

Triple and quadruple NRTI / NtRTI combinations without protease inhibitors or non-nucleoside reverse transcriptase inhibitors in first-line therapy are discussed in What to start with in Anti-HIV therapy: Choosing a combination.

To compare all antiretroviral drugs licensed in the European Union, see NAM's drug chart. The chart contains illustrations of the drugs, as well as information on drug doses, formulations, pill burdens, main side-effects and food restrictions.

Comparing efficacy

Several studies have compared dual NRTI / NtRTI combinations, with or without an additional drug, in people new to treatment. Most of the randomised studies have compared d4T (stavudine, Zerit)-containing regimens with AZT- or tenofovir-containing regimens, often showing similar efficacy between combinations. However, the usefulness of many of these studies, such as Ozcombo, START I and II and ALBI, has now been diminished by the discovery of long-term toxicities associated with d4T, such as fat loss (Carr 2000; Eron 2000; Squires 2000).

In the United Kingdom, d4T is no longer recommended as first-line therapy. Long-term toxicities are now a key factor in the selection of antiretrovirals, along with efficacy, dosing and short-term toxicity data.

While many NRTI / NtRTI combinations have shown few differences in efficacy, the combination of tenofovir and ddI has shown poor CD4 cell count response rates in many studies, as well as elevated risks of ddI-related side-effects. This combination is not recommended.

Details on the relative efficacy of NRTI / NtRTI backbones are given in the sections below.

Central nervous system penetration

The body protects the central nervous system (CNS) from harm by making it difficult for many substances to pass from the bloodstream into the tissues or surrounding fluid of the brain and spinal cord. This is known as the blood-brain barrier. However, HIV does infect the CNS, so the ideal anti-HIV drug should be able to cross this barrier. If only a small amount of drug crosses into the brain, it may not be sufficient to suppress the virus fully, and might even hasten the emergence of drug-resistant HIV strains in the CNS.

Of all the currently licensed NRTIs, AZT penetrates the CNS most effectively, and has been linked to a substantially reduced risk of developing HIV brain disease such as dementia. Abacavir also crosses the blood-brain barrier effectively, but has not been shown to reduce brain HIV levels (Lanier 2001).

Small studies have suggested that d4T, 3TC and ddI also cross the blood-brain barrier to some extent, but their effectiveness against dementia has not been proven. One study has shown that whilst a 40mg twice-daily dose of d4T maintains drug levels in the spinal fluid which are high enough to stop HIV replication, lower doses do not do so reliably.

Resistance

Understanding of the evolution of resistance patterns in people taking NRTIs continues to grow. As mentioned above, d4T and AZT are now regarded as cross-resistant. Also, since they work in similar ways to inhibit HIV replication, their use together is not recommended. This restriction also applies to FTC and 3TC.

Resistance is discussed in detail in Resistance to nucleoside and nucleotide reverse transcriptase inhibitors in Anti-HIV therapy: Resistance.

Dosing considerations

All the NRTIs and NtRTIs are taken once or twice a day. Tenofovir, ddI, 3TC, abacavir and FTC can be taken once a day. In addition to this low dosing frequency, they have a low pill burden, with a small number of tablets or capsules that need to be taken every day.

The production of the fixed-dose combination tablets Combivir, Kivexa and Truvada has further simplified dosing of the NRTIs and NtRTIs. Patients taking these combinations need only take one tablet once or twice each day.

Side-effects

The NRTIs and NtRTIs have different side-effect profiles which may be an important factor in choosing a backbone. In general, 3TC appears to be better tolerated than many other NRTIs, partly accounting for its inclusion in many regimens. Tenofovir and FTC are also well tolerated, with the Gilead 934 study showing that tenofovir plus FTC performed better than AZT plus 3TC mainly because it was better tolerated (Pozniak 2005).

There has been a trend away from d4T due to its association with fat loss side-effects, with current British HIV Association guidelines recommending against d4T in first-line therapy (Gazzard 2005). There is also accumulating evidence for a role of AZT in producing fat loss, although this is probably less rapid than that seen with d4T. See Anti-HIV therapy: Body fat and metabolic changes whilst on treatment for further information on this topic.

Nausea and vomiting are common side-effects which can usually be controlled with medication that can be prescribed before starting treatment. AZT, ddI and abacavir are more strongly associated with nausea and vomiting than other NRTIs.

Other side-effects may require you to discontinue the drug which is causing the problem. For example, peripheral neuropathy has been more strongly associated with d4T, ddC and ddI in large randomised studies. If peripheral neuropathy develops on one of these three drugs, it is likely that it could be made worse by any of the remaining 'd' drugs. The risk of peripheral neuropathy is increased when d4T/ddI are taken concurrently, and that risk is enhanced by the addition of hydroxycarbamide (Hydrea; Moore 2001). The risk was also greater among people with lower CD4 counts. See Neuropathy in Symptoms and illnesses: A to Z of illnesses for further details.

Other serious side-effects include pancreatitis, which is often associated with ddI treatment, and a life-threatening hypersensitivity reaction in patients starting abacavir treatment. For more information, see ddI - overview and Abacavir - overview in Drugs used by people with HIV: Nucleoside reverse transcriptase inhibitors and Pancreatitis in Symptoms and illnesses: A to Z of illnesses.

Lactic acidosis is a complication of NRTI therapy in approximately 1% of individuals, and is life-threatening. All NRTIs have been associated with an increase in liver enzyme levels in clinical trials, but lactic acidosis has been very rare. See Lactic acidosis / acidaemia in Symptoms and illnesses: A to Z of illnesses for further details.

Kidney toxicity and Fanconi syndrome, which may damage the kidneys and eventually weaken the bones, may be rare but serious side-effects of tenofovir. Creatinine levels and creatinine clearance should be monitored carefully prior to starting tenofovir treatment and whilst the drug is being taken for any signs of reduced kidney function or kidney damage.

AZT plus 3TC

AZT plus 3TC is one of the most frequently studied combinations, and has been the most frequently prescribed NRTI backbone in the United Kingdom (Curtis 2003). Its popularity can be explained by its tolerability and convenience, since the two drugs can be taken in one tablet as Combivir.

The main side-effects tend to occur soon after starting treatment, and usually become easier to live with. Nausea, headache and gastrointestinal upsets are the commonest side-effects associated with this combination, and are probably due to the AZT component. Anaemia is also a rare side-effect of AZT treatment, and the drug may eventually lead to fat loss. This long-term side-effect may eventually lead to other NRTI combinations being preferred over AZT plus 3TC in first-line therapy.

The combination of AZT and 3TC has been shown to have similar virological efficacy to abacavir plus 3TC and to tenofovir plus FTC (DeJesus 2004; Pozniak 2005). However, in comparison to tenofovir plus FTC, both in combination with efavirenz, there were higher rates of discontinuation in the AZT plus 3TC arm of the trial, and less impressive CD4 cell count rises, although this was driven by higher rates of discontinuation in the AZT plus 3TC arm.

Older studies examining the efficacy of this combination of NRTIs have generally compared it to d4T-containing regimens. These include the Ozcombo, START I and II and ALBI trials, showing similar rates of viral load reductions to d4T with 3TC and d4T with ddI (Carr 2000; Eron 2000; Squires 2000). Similarly, the ACTG 384 study showed that starting treatment with AZT, 3TC and efavirenz resulted in more durable viral load suppression than treatment with d4T, ddI and efavirenz, although there was no difference in the likelihood of viral load rebound when comparing these two NRTI backbones paired with nelfinavir (Shafer 2003). Results from 'real life' have confirmed the superiority of AZT plus 3TC over d4T plus ddI when combined with efavirenz (Suá²¥z-Lozano 2003).

However, the recommendation that d4T not be used in first-line therapy due to long-term side-effects has reduced the importance of these comparisons, with current guidelines recommending AZT plus 3TC as a first-line NRTI backbone.

3TC plus abacavir

3TC plus abacavir has proved to be a more potent NRTI backbone in children than AZT plus 3TC, and recent results suggest 3TC plus abacavir may also be a superior NRTI backbone in adults. This combination is available as a once-daily fixed-dose tablet, called Kivexa in Europe and Epzicom in the United States.

The combination of 3TC and abacavir has been shown to have similar virological efficacy to AZT plus 3TC (DeJesus 2004). CNA30024 randomised 649 previously untreated people to AZT plus 3TC or abacavir plus 3TC, both combined with efavirenz. Results after a year of treatment show the effect on viral load was equivalent but abacavir produced a significantly greater rise in CD4 T-cells. However, there has been no head-to-head comparison of 3TC plus abacavir with FTC plus tenofovir.

Other non-comparative data have also been encouraging. In ESS30009, once daily 3TC, abacavir and efavirenz produced viral suppression in over 90% of recipients after only eight weeks of treatment (Gallant 2003) and the CLASS study showed 3TC plus abacavir was well tolerated (Bartlett 2004). Good results have also been shown when these NRTIs are combined with ritonavir-boosted fosamprenavir (Gathe 2004).

One potential drawback of 3TC plus abacavir is the possibility hypersensitivity reactions to abacavir, which tend to occur in around 5 to 8% of recipients. For more information, see Abacavir - overview in Drugs used by people with HIV: Nucleoside reverse transcriptase inhibitors.

FTC plus tenofovir

FTC and tenofovir have been combined in a once daily tablet called Truvada. The combination of tenofovir plus FTC has been shown to have similar virological efficacy to AZT plus 3TC (Pozniak 2005). However, there has been no head-to-head comparison of FTC plus tenofovir to 3TC plus abacavir.

A head-to-head comparison with AZT plus 3TC has reported 24-week preliminary results, showing that a higher proportion of patients receiving FTC plus tenofovir had viral loads below 400 copies/ml at week 48. This difference appears to be driven chiefly by differences in tolerability, with a higher rate of discontinuation in the AZT and 3TC arm due to adverse events (Pozniak 2005). Data have also been collected to 114 weeks, showing continued virological benefits of this combination.

FTC is a very similar drug to 3TC. Therefore, the results of the Gilead 903 study, which compared d4T to tenofovir, both combined with 3TC and efavirenz, are often used as evidence for a beneficial effect of FTC plus tenofovir over d4T plus 3TC or FTC. While the two combinations gave similar results in terms of viral load suppression, tenofovir recipients had lower increases in blood fats and experienced gains in fat under the skin, in contrast to d4T recipients who experienced fat loss (Miller 2003; Pozniak 2003; Staszewski 2003).

Although there are some concerns regarding possible deleterious effects of tenofovir on kidney function and bone density, these problems have not been seen in all trials. Further research is required to identify whether these are true side-effects of tenofovir treatment.

The development of the K65R mutation is another potential concern with this backbone. This may limit future treatment options.

3TC plus tenofovir

3TC is a very similar drug to FTC, so many of the benefits and drawbacks of FTC plus tenofovir apply to 3TC plus tenofovir. Both drugs can be dosed once daily, and taken at the same time with food. In the United Kingdom, tenofovir and 3TC are recommended first-line treatments for people co-infected with HIV and hepatitis B.

The large, randomised 903 study compared tenofovir with d4T in combination with 3TC and efavirenz showed equivalence between the two regimens (Pozniak 2003). However, 3TC is better tolerated than d4T, which can cause fat loss and peripheral neuropathy.

One randomised trial has shown that 3TC plus tenofovir has similar efficacy to 3TC or abacavir plus ddI, but with a lower incidence of resistance mutations than abacavir plus ddI (Maggiolo 2005).

d4T plus 3TC

The combination of d4T plus 3TC has also been widely prescribed, on the grounds that it is better tolerated than AZT plus 3TC. However, head-to-head comparisons of the two combinations have failed to show any differences in efficacy or tolerability (Carr 2000). It also has similar levels of effectiveness to 3TC plus tenofovir or abacavir (Gallant 2004; Podzamczer 2004b).

However, due to the association of d4T with fat loss, it is no longer recommended in first-line therapy.

ddI plus tenofovir

Although both ddI and tenofovir can be taken once a day, the combination of these two drugs is not recommended for two main reasons.

• Taking the two drugs together can increase the risks of developing side-effects related to ddI.

• A number of studies have shown unexpected CD4 cell count declines in patients taking the drug together.

A Spanish study of 150 patients who took the drugs together at the correct dose for their weight found that only 15% had a CD4 cell count increase in the 48 weeks after starting the combination, and 30% had a CD4 cell count decline of between 101 and 200 cells/mm³ (Barrios 2004; Negredo 2004, 2005). Further data are needed in order to understand whether this phenomenon is restricted to particular sub-groups of patients and whether it is chiefly a consequence of using the 400mg dose of ddI rather than the 250mg dose. In addition, it remains to be determined whether the combination of these drugs with a boosted protease inhibitor may prevent this CD4 cell count decline from occurring, as suggested in an observational study (Khanlou 2005).

High rates of virological failure were also seen in patients starting treatment with ddI, tenofovir and efavirenz (Podzamczer 2004a). Another open-label comparative trial in which patients were randomised to receive ddI and efavirenz with either tenofovir or 3TC was stopped early because higher rates of treatment failure were seen in patients taking tenofovir. These viral rebounds tended to occur in patients who had a baseline CD4 cell count below 200 cells/mm³ and a pre-treatment viral load above 100,000 copies/ml (Maitland 2005).

These findings were communicated to United States doctors in a letter from ddI manufacturer Bristol-Myers Squibb and Gilead Sciences, the manufacturers of tenofovir, warning of the risk of early failure when these drugs are combined with an NNRTI. It remains to be determined whether they can be taken with a PI.

Patients taking tenofovir and ddI together should be monitored closely for ddI-associated toxicities such as pancreatitis, lactic acidosis and peripheral neuropathy. See ddI - overview in Drugs used by people with HIV: Nucleoside reverse transcriptase inhibitors and Tenofovir - overview in Drugs used by people with HIV: Nucleotide reverse transcriptase inhibitors for more details.

ddI plus 3TC

Although 3TC plus ddI is an attractive combination from the point of view of adherence, since both drugs can be taken together once a day, evidence showing that ddI can be used after the emergence of 3TC resistance suggests that ddI is best spared for use in second-line therapy. ddI is also a difficult drug to take as it must be taken on an empty stomach. Use of ddI also runs the risk of long-term toxicities such as pancreatitis and neuropathy.

Nevertheless, ddI plus 3TC is an effective NRTI backbone, with similar efficacy to 3TC plus tenofovir and ddI plus abacavir, but with a lower incidence of the development of resistance mutations than ddI plus abacavir (Maggiolo 2005).

ddI plus FTC

FTC is a very similar drug to 3TC, so has a similar set of benefits and drawbacks to ddI plus 3TC.

One randomised, double-blind study comparing the use of FTC and d4T in combination with ddI and efavirenz showed that people receiving FTC were significantly less likely to stop treatment due to side-effects and more likely to have viral load below 50 copies/ml and had higher CD4 cell count gains after 24 weeks (Saag 2004). FTC treatment is also associated with a reduced risk of developing the MI84V mutation if viral load rebounds, when compared with 3TC.

However, the food restrictions and possible long-term side-effects of ddI may make this backbone less attractive to patients starting treatment.

AZT plus ddI

AZT plus ddI is now little used in first line therapy, although several large studies have shown that it is more effective than AZT plus ddC. There are no data on the use of AZT with enteric-coated ddI.

Tenofovir plus abacavir

This combination has not been evaluated in patients starting treatment and is not recommended.

Abacavir plus ddI

This combination has only been evaluated in one randomised trial, with interim 24-week results published at a recent conference. Although this trial showed that it had similar efficacy to 3TC plus ddI or tenofovir, there was a trend towards more virologic failure and discontinuations in the abacavir plus ddI arm, as well as a higher incidence of resistance mutations (Maggiolo 2005). However, longer term follow-up is required before robust conclusions can be drawn from this study.

d4T plus ddI

d4T plus ddI is less well tolerated than either AZT plus 3TC or d4T plus 3TC, due in part to higher rates of peripheral neuropathy when the two drugs are used together. Current United Kingdom guidelines recommend that d4T not be used in first-line therapy.

In the United States, d4T plus ddI has been added to the list of antiretroviral components which should not be offered at any time due to the increased risk of toxicities. United States guidelines only recommend the use of d4T plus ddI where potential benefits outweigh the risk of toxicities.

Efficacy studies have come up with conflicting results. Whilst studies conducted a number of years ago, such as ALBI, START II and Ozcombo found no difference, or even a slight advantage of d4T plus ddI with AZT plus 3TC when combined with indinavir, the more recent ACTG 384 study found that d4T plus ddI was inferior to AZT plus 3TC when paired with efavirenz (Carr 2000; Eron 2000; Squires 2000). ACTG 384 also showed that d4T plus ddI was associated with significantly greater fat loss than AZT plus 3TC, while the FIRST study showed that it resulted in more fat loss, increased blood fat and insulin levels and insulin resistance than abacavir plus 3TC (Shafer 2003; Shlay 2005).

AZT plus ddC

This combination has been little used since two studies reported in 1995 both found that it was inferior to AZT plus ddI.

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