Current concerns in HIV antiretroviral therapy

teaser

Carlo Torti
MD
Consultant Physician

Valeria Tirelli
Postgraduate
internal student

Eugenia Quiros-Roldan
MD PhD
Consultant Physician

Giampiero Carosi
MD
Research and
Clinical Director
Institute of Infectious and Tropical Diseases
University of Brescia
School of Medicine
Brescia
Italy
E:[email protected]

The primary objective of antiretroviral therapy is to achieve maximal and durable suppression of HIV replication, restore immunological function, improve patient quality of life and reduce HIV-related morbidity and mortality. Highly active antiretroviral therapy (HAART) has markedly improved the prognosis of HIV-infected patients by controlling HIV replication.(1) However, as HAART cannot eradicate the infection, lifelong therapy is still needed. With increasing time on HAART, new problems are emerging, such as cumulative toxicity and HIV drug resistance emergence.

Since the introduction of HAART, more therapeutic options have been made available – with the development of new antiretroviral agents – but new strategies to reduce side-effects and manage the emergence of viral resistance are urgently needed.

Available drugs and their mechanism of action
Antiretroviral agents act by inhibiting different proteins, such as reverse transcriptase, protease and gp41, that are crucial for HIV replication.

Four classes of antiretroviral drugs that permit a high number of combination regimens are currently available:

• Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs), which act through a mechanism of “chain termination”: the activated drug is incorporated into the viral DNA chain and blocks reverse transcription through a mechanism of suicide inhibition.
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs), which inhibit reverse transcriptase through a different mechanism, by changing its three-dimensional structure.
• Protease inhibitors (PIs), which inhibit the protease enzyme, allowing viral maturation process outside the infected cells after HIV budding.
• Fusion inhibitors (FIs). In this new class, only T-20 (enfuvirtide) is currently available. This drug inhibits HIV-1 viral attachment on the surface of target cells before entry, and it may be the predecessor for the development of e-HAARTs (extracellular HAARTs). The TORO studies enlisted treatment-experienced patients whose virus was not being controlled by  their current regimen.(2,3) Regimens with T-20 added in were compared with “Optimized Regimen Only” (ORO). These studies showed that the addition of T-20 improved viroimmunological outcome in patients who had received multiple antiretroviral agents and had multidrug- resistant HIV-1 infection.

Current guidelines highlight the pros and cons of combination regimens in first-line use (naive patients). It is generally very important in drug selection to individualise the best for a patient, based on the advantages and disadvantages of each drug combination (such as pill burden, dosing frequency, toxicities and drug–drug interactions) and patient conditions (such as pregnancy, comorbid conditions and level of plasma HIV-RNA and CD4+ T-cell count at baseline).(4)

Current problems
Antiretroviral therapy fails to control HIV replication in an increasing number of patients, due to several causes. There is now substantial evidence that the emergence of HIV drug resistance is a leading cause, as well as a consequence, of antiretroviral therapy failure.(5–8) Several factors contribute to the emergence of viral resistance:

• HIV-1 characteristics, especially high proliferation turnover (1,010 virions produced/day) and lack of proofreading ability (ie, viral inability to correct nucleotide matching errors during the reverse transcription process).
• Drug characteristics: low genetic barrier (number of mutations needed to confer resistance) and suboptimal potency of the regimen as a whole.
• Patient characteristics: poor adherence to antiretroviral regimens, or poor drug absorption or accelerated drug clearance.

Adherence is another key determinant for sustained virological suppression.(9) HIV disease management should therefore focus on increasing adherence through the following interventions:

• Reduce dose frequency and number of pills.
• Simplify food requirements.
• Inform patients on the side-effects and their management and prevention.
• “Recruit” family and friends to support patients during the course of their treatment plan.

Adverse events associated with antiretroviral therapy can make adherence difficult. Adverse events linked to NRTIs are mainly related to mitochondrial dysfunction (such as peripheral neuropathy, pancreatitis, lactic acidosis or liver steatosis).(10) In particular, lactic acidosis is a severe adverse event that manifests with nonspecific gastrointestinal symptoms and, sometimes, with dyspnoea, which should lead to the prompt suspension of the antiretroviral therapy. A recent paper has shown that switching from some NRTIs (stavudine or didanosine) to others (especially abacavir) may prevent lactic acidosis relapse.(11)

One of the main adverse events associated with NNRTIs is skin rash, frequently related to nevirapine use. Rare cases of Stevens–Johnson syndrome have also been reported with the use of all three currently available NNRTIs. However, the pattern of toxicity is largely drug-specific (with more neuropsychological effects with efavirenz and more hepatotoxicity events with nevirapine). Among all patients enrolled in the prospective 2NN study,(12) 2.1% in the nevirapine arm vs 0.3% in the efavirenz arm had a grade 3/4 clinical hepatotoxicity, and 7.8% in the nevirapine arm vs 4.5% in the efavirenz arm had a grade 3/4 laboratory hepatobiliary toxicity. Two deaths (due to toxic hepatitis and Stevens–Johnson syndrome) were attributed to nevirapine. Therefore, the choice of a drug should be tailored to the patient’s condition, although effectiveness was similar in the two comparative arms of the study.(12)

Adverse effects associated with the use of PIs are typically gastrointestinal. Indeed, gastrointestinal intolerance is the most frequent adverse event that occurs during HAART. Moreover, these drugs can affect glucose metabolism, lipid profile and fat redistribution.(13) Cases of worsening glucose intolerance among patients with pre-existing diabetes, and also new onset of diabetes, have been related to the use of all PIs.(14) Fat redistribution (ie, lipodystrophy) and lipid abnormalities increase remarkably with the use of any PI in up to 50% of patients. Patients with hypertriglyceridaemia or hypercholesterolaemia should therefore be carefully evaluated for cardiovascular risk and pancreatitis, as these conditions are the main adverse consequences of hyperlipidaemia. Interventions should include dietary modifications, lipid-lowering agents or PI discontinuation. Worryingly, it has been estimated from a large observational cohort that risk of myocardial infarction increases by 26% for each year of exposure to PIs.(15)

Future directions
New strategies are being developed to prolong the benefits and reduce the side-effects of current antiretroviral regimens. An important question is to determine which drugs to use in the first regimen. The ACTG 384 study(16) compared an NNRTI (efavirenz) with a PI (nelfinavir). The study demonstrated that efavirenz-containing regimens provided better chances of virological suppression at the end of the observation period than nelfinavir-containing ones. However, one important limitation of this study is the lack of comparison with boosted PI-containing regimens, information that is not available in the current literature. Such boosted PI-containing regimens are designed to reduce PI hepatic clearance by inhibiting CYP3A4 liver enzymes through the addition of subtherapeutic doses of ritonavir, thus allowing significant increases in bioavailability of the boosted PI. Indeed, a recent study demonstrated that liponavir–ritonavir was superior to nelfinavir-
containing regimens.(17)

Induction–maintenance therapy has been proposed to improve treatment adherence and reduce the emergence of drug-resistant mutations. This strategy is based on the use of potent induction regimens followed by maintenance treatments that are simpler and better tolerated in the long term. In the INDUMAIN study,(18) a cohort of naive patients received a four-drug induction treatment including two NRTIs and two PIs followed by a three-drug maintenance therapy with two NRTIs and one NNRTI. This study showed that induction–maintenance regimens are well tolerated and associated with HIV-1 virological suppression in the long term. Finally, the FORTE trial first demonstrated the superiority of an induction–maintenance regimen over a standard regimen containing two NRTIs and one NNRTI in terms of virological response.(19)

Treatment rotation is another new therapeutic strategy based on alternation of different therapeutic regimens. Its objective is to hamper the emergence of resistant strains since selective pressure is intermittent, precluding the accumulation of resistance mutations to individual drugs and classes. In the SWATCH study,(20) patients were randomised to receive two NRTIs and one NNRTI or two NRTIs and one PI until virological failure, or to “alternate” between these two regimens every three months while viral load was still suppressed. The virological outcome was better in the alternating therapy arm than in the standard-of-care arm, while side-effects and adherence features were similar.

Major factors contributing to the durability of initial regimens include antiviral potency, as well as tolerability and patient adherence to treatment. Thus, the focus of HIV treatment has shifted toward the use of regimens as simple as possible. In this regard, a major strategy is once-a-day therapy to improve convenience and optimise adherence without compromising virological suppression. Once-a-day regimens have been made feasible by the availability of antiviral drugs that can be administered once-a-day.(21) Finally, due to several side-effects, nonadherence and the emergence of resistant variants, stopping the antiretroviral therapy and structured treatment interruptions (STIs) have been proposed. The rationale for STI in individuals with acute HIV infection is the stimulation of HIV-specific CD4+ T-cell response, so as to convert acutely infected patients into long-term nonprogressors. This objective is currently considered unrealistic; however, some acutely infected patients may still benefit from such a strategy.(22) By contrast, STI in chronically infected patients is more focused on the limitation of chronic drug toxicities by reducing exposure to HAART. In the BASTA trial,(23) the efficacy of STI as a strategy in HIV management was tested. The only significant predictor of CD4+ cell decline after stopping therapy was the nadir CD4 T-cell count: median time to restart therapy was 6.9 months for those with a T-cell nadir of <200/mm(3), 14.1 months for those with a T-cell nadir of 200–350/mm(3), and 17.8 for those with a T-cell nadir of 350–500/mm(3). Interestingly, no patients with a nadir of >500 T-cells/mm(3) had to restart treatment, suggesting that such a strategy is indeed possible in patients who started HAART early. However, potential risks of STI include CD4+ T-cell decline, increase in HIV transmission and development of drug resistance if drugs with longer half-lives are stopped simultaneously. Thus, the cost-effectiveness of STI is still controversial.(24) There is an ongoing debate on whether STI use increases the efficacy of salvage therapy intervention in patients harbouring multidrug-resistant HIV strains who have persistent plasma viraemia. In such circumstances, the primary goal is to allow the re-emergence of wild-type HIV, which may respond better after antiretroviral therapy re-initiation. There are currently conflicting results on this strategy: Katlama et al(25) have demonstrated more benefits than risks, whereas other authors have demonstrated important drawbacks (ie, increase in disease progression rates and lack of viroimmunological benefits after salvage therapy re-initiation).(26,27)

Antiretroviral drugs in the pipeline
There is an urgent need for therapeutic agents targeting new molecules and/or characterised by a more favourable toxicity–tolerability–pill burden profile. Promising agents in development include:

• New NRTIs, such as emtricitabine (FTC), which is a fluorinated cytidine analogue similar to lamivudine but with enhanced potency.(28)
• New NNRTIs, such as TMC-125 (Tibotec), which is effective against HIV-resistant variants that harbour 100I, 103N, 181C, 188L and/or 190A/S mutations (these mutations conferring viral resistance to other NNRTIs).(29)
• New PIs, in particular fosamprenavir, a prodrug of amprenavir that may be effective against PI-resistant HIV mutants when used in ritonavir-boosted regimens.
• New fusion inhibitors, such as T-1249, which is derived from T-20 but may act on T-20-resistant variants. In addition, this drug has a long half-life in the blood and, hence, it is taken once-daily.
• Entry inhibitors, such as chemokine receptor antagonists. These drugs, which inhibit CCR5 or CXCR4 used by HIV to enter the target CD4+ T-cells, include AK-602, TAK-220, TAK-779 and UK-427,857 (CCR5 inhibitors), and AMD-070, AMD-31000 and ALX40-4C (CXCR4 inhibitors).
• Integrase inhibitors, which, by inhibiting integrase, obstruct the integration of HIV in the cellular DNA. These drugs include DCQA/DCTA, Zintevir, S-1360 and HE-2000.

Conclusion
The emergence of multidrug-resistant strains and several side-effects of antiretroviral therapy are of increasing concern and reduce the effectiveness of HAART. Among the adverse effects, metabolism modification and mitochondrial toxicity are now in the limelight, as they can lead to cardiovascular risks. New drugs and strategies are needed to improve the quality of life of HIV-1 positive patients, reduce disease progression and hamper the emergence of viral resistance.

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