Noninfectious HIV-related Comorbidities and HAART Toxicities: Choosing Alternative Antiretroviral Strategies

Lidia Gazzola; Camilla Tincati; Antonella d'Arminio Monforte

HIV Ther. 2010;4(5):553-565.

Noninfectious HIV-related Comorbidities: The Premature aging Process in HIV-infected People

In the HAART era, most patients taking medication achieve a complete and most likely lifelong virologic suppression, and thus, the classic AIDS-related conditions are becoming less common, with a dramatic drop in overall mortality.^[1–3]

However, despite the apparently full control of HIV infection by HAART, clinical evidence has demonstrated that HAART does not completely restore health in HIV-infected patients, who are affected by an increased risk of several non-AIDS complications.^[4]

A twofold increase in the relative risk of myocardial infarction (MI) has been observed in the HIV-positive population compared with HIV-uninfected patients,^[5–7] as well as a three-times greater prevalence of osteoporosis.^[8] Furthermore, renal diseases affect HIV-infected people: black HIV-positive patients are more likely to develop chronic kidney failure, and HIV-infected individuals have a decreased glomerular filtration rate and increased prevalence of microalbuminuria than matched HIV-uninfected controls.^[9]

These noninfectious HIV-related comorbidities are tied together and are the expression of a physiologic aging process, even though they occur at an earlier age, undermining life expectancy in the HIV-infected population.^[10]

These clinical findings probably arise from the failure of HAART to repair all immune damage consequent to HIV infection. Indeed, HIV-infected patients undergoing HAART, despite full virologic control, maintain a hyper-activated immunological profile, which is sustained by HIV and non-HIV-related antigens and is associated with reduced naive and central memory subsets, in favor of T-cell senescence.^[11–13] These immunological alterations are similar to those associated with age in the HIV-uninfected elderly population, and have led to hypotheses that an accelerated process of immune senescence and inflammatory aging takes place during HIV infection, as evidenced by the increased risk of age-related diseases and 'frailty'.^[14,15]

As treating clinicians, we have to deal with the changing spectrum of HIV-associated disease, and modifications in the medical management of HIV infection are thus advocated. In particular, there is an increasing need to strictly consider premature age-associated complications when choosing a tailored antiretroviral (ARV) therapy regimen. This article aims to explore the impact of standard HAART regimens on the different noninfectious HIV-related comorbidities. Metabolic, cardiovascular, bone and renal diseases, with the exclusion of liver complications, will be assessed together with the currently available and more recent alternative ARV strategies in order to summarize the state of the art and its clinical implications.

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Table 1. Overview of the major studies evaluating efficacy, safety and tolerability of nucleoside reverse transcriptase inhibitor-sparing regimens.
Study (year)	Design and study population	NRTI-sparing regimen	Control regimen	Virologic end point and efficacy	Safety and tolerability	Ref.
*NRTI-sparing regimens based on combination of PI and NNRTI*
Staszewski et al. (1999)	Randomized controlled trial; 450 patients naive to 3TC, NNRTI and PI with HIV-RNA >10,000 cp/ml	IDV plus EFV	EFV plus AZT/3TC; IDV plus AZT/3TC	Percentage of patients with HIV-RNA <400 cp/ml at week 48; ITT analysis: IDV plus EFV 53% vs EFV plus AZT/3TC 70% (p < 0.05); IDV plus AZT/3TC 48%	Discontinuation due to AE: IDV plus EFV 7% vs EFV plus AZT/3TC 7% IDV plus AZT/3TC 20% (p < 0.001)	[58]
Negredo et al. (2005)	Pilot, open-label, prospective study; 31 ARV-experienced patients with HIV-RNA <80 cp/ml	LPV/r plus NVP	LPV/r plus two NRTIs	Percentage of patients with HIV-RNA <80 cp/ml at week 48; ITT analysis: LPV/r plus NVP 87.5% vs LPV/r plus two NRTIs 100% (p = 0.5)	No discontinuation due to AE; LPV/r plus NVP increased chol HDL and apo-AI; Increased mtDNA content and respiratory mitochondrial chain enzyme activity in LPV/r plus NVP	[59]
Allavena et al. (2005)	Pilot, single-arm, open-label, prospective study; 86 patients (65 ARV-naive and 21 ARV-experienced NNRTI-naive) with HIV-RNA >5000 cp/ml	LPV/r plus EFV	None	Percentage of patients with HIV-RNA <50 cp/ml at week 48; ITT analysis: LPV/r plus EFV 69%	Discontinuation due to AE: LPV/r plus EFV 8% Fasting lipid levels increased at week 48	[62]
Riddler et al. (2008)	Randomized controlled trial; 757 ARV-naive patients with HIV-RNA >2000 cp/ml	LPV/r plus EFV	EFV plus two NRTIs; LPV/r plus two NRTIs	Percentage of patients with HIV-RNA <50 cp/ml at week 96; ITT analysis: LPV/r plus EFV 83% vs EFV plus two NRTIs 89% LPV/r plus two NRTIs 77% (p = 0.003)	No difference in discontinuation due to AE; Lipoatrophy by DEXA: LPV/r plus EFV 9% vs EFV plus two NRTIs 32% (p < 0.02) LPV/r plus two NRTIs 17%; Greater increase in total cholesterol	[63]
*Randomized controlled trials on NRTI-sparing regimens based on PI monotherapy*
Arribas et al. (2005)	Randomized controlled trial; 42 patients on LPV/r plus two NRTIs with HIV-RNA <50 cp/ml	LPV/r b.i.d.	LPV/r plus two NRTIs	Percentage of patients with HIV-RNA <50 cp/ml at week 48; ITT analysis: LPV/r 81% vs LPV/r plus two NRTIs 95% (p = 0.34)	No difference in discontinuation due to AE; No difference in fasting lipid levels at week 48	[64]
Pulido et al. (2008)	Randomized controlled trial; 205 patients on LPV/r plus two NRTIs with HIV-RNA <50 cp/ml;	LPV/r b.i.d.	LPV/r plus two NRTIs	Percentage of patients with HIV-RNA <50 cp/ml at week 48; ITT analysis: LPV/r 85% vs LPV/r plus two NRTIs 90% (p = 0.31)	No difference in discontinuation due to AE; No difference in fasting lipid levels at week 48	[65]
Cameron et al. (2008)	Randomized controlled trial; 155 ARV-naive patients with HIV-RNA >1000 cp/ml	LPV/r b.i.d. (after induction with LPV/r plus AZT/3TC)	EFV plus AZT/3TC	Percentage of patients with HIV-RNA <50 cp/ml at week 96; ITT analysis: LPV/r 48% vs EFV plus AZT/3TC 61% (p = 0.17)	No difference in discontinuation due to AE; Percentage of patients with lipoatrophy at week 96: LPV/r 5% vs EFV plus AZT/3TC 34% (p < 0.001)	[66]
Delfraissy et al. (2008)	Randomized controlled trial; 136 ARV-naive patients with HIV-RNA <100,000 cp/ml	LPV/r b.i.d.	LPV/r plus AZT/3TC	Percentage of patients with HIV-RNA <50 cp/ml at week 48; ITT analysis: LPV/r 67% vs LPV/r plus AZT/3TC 75% (p = 0.34); On treatment analysis: LPV/r 84% vs LPV/r plus AZT/3TC 98% (p = 0.03)	No difference in discontinuation due to AE	[68]
Arribas et al. (2010)	Randomized controlled trial; 256 patients on NNRTI- or PI-based therapy with HIV-RNA <50 cp/ml	DRV/r q.d.	DRV/r q.d. plus two NRTIs	Percentage of patients with HIV-RNA <50 cp/ml at week 48; ITT analysis: DRV/r 84.3% vs DRV/r plus two NRTIs 85.3%; per protocol population: DRV/r 86.2% vs DRV/r plus two NRTIs 87.8%	No difference in discontinuation due to AE	[71]
Katlama et al. (2009)	Randomized controlled trial; 225 patients on DRV/r b.i.d. plus two NRTIs with HIV-RNA <400 cp/ml	DRV/r b.i.d.	DRV/r plus two NRTIs	Percentage of patients with HIV-RNA <50 cp/ml at week 48; ITT analysis: DRV/r 87.5% vs DRV/r plus two NRTIs 92%; per protocol population: DRV/r 94.2% vs DRV/r plus two NRTIs 99%	No difference in discontinuation due to AE	[72]
*NRTI-sparing regimens with drugs from new antiretroviral classes*
Ripamonti et al. (2009)	Pilot, open-label, prospective study; 27 ARV-experienced patients	RGV plus ATV	None	Percentage of patients with HIV-RNA <50 cp/ml at week 24 RGV plus ATV 96%	No significant change in lipid profile; mean total bilirubin 2.0 mg/dl	[81]

3TC: Lamivudine; AE: Adverse effect; ARV: Antiretroviral; ATV: Atazanavir; AZT: Zidovudine; b.i.d.: Twice daily dose; Chol: Cholesterol; DRV/r: Darunavir/ritonavir; EFV: Efavirenz; HDL: High-density lipoprotein; IDV: Indinavir; ITT: Intention to treat; LPV/r: Lopinavir/ritonavir; NNRTI: Non-nucleoside reverse transcriptase inhibitor; NRTI: Nucleoside reverse transcriptase inhibitor; NVP: Nevirapine; PI: Protease inhibitor; q.d.: Every day; RGV: Raltegravir.

Sidebar

Executive Summary

Noninfectious HIV-related comorbidities

In the HAART era, HIV-infected patients are increasingly affected by comorbidities, which are the expression of a premature aging process. Clinicians have to tailor antiretroviral (ARV) treatment in order to achieve immune-virologic efficacy without worsening patients' underlying clinical conditions.

The impact of actual HAART regimens on noninfectious HIV-related comorbidities

Metabolic syndrome: the effects of nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs) and non-NRTIs (NNRTIs) on lipodystrophy, insulin resistance and dyslipidemia are addressed by the review of the main clinical trials on HAART metabolic outcome.
Cardiovascular complications: data on the relationship between increased risk of myocardial infarction and HAART (PI cumulative exposure and recent exposure to abacavir) are discussed.
Bone metabolism disorders: HIV-infection, ARV exposure, and PI-based regimens have been associated with increased prevalence of osteoporosis. We report data from ACTG 5224, evaluating the impact of different backbones and of PI- versus NNRTI-based regimens on bone mineral density reduction.
Renal diseases: ARV-related renal side effects have been described with PIs (indinavir and ATV) and TDF. Conflicting data on the risk associated with these drugs, with particular regard to data from the EuroSIDA cohort of an increased risk of chronic kidney disease, are discussed.

Novel antiretroviral strategies: trials evaluating immune–virologic efficacy & tolerability of NRTI-sparing regimens have been reviewed

An overview on the clinical trials on NNRTI plus boosted-PI regimens is provided. ACTG 5142 demonstrated a similar virologic efficacy of lopinavir/ritonavir plus efavirenz compared with the standard-of-care, however this regimen was associated with an increased frequency of lipid elevation together with a higher risk of NNRTI resistance.
Several studies have been conducted to date on boosted-PI monotherapy. Despite a meta-analytic review demonstrating the inferior virologic efficacy of lopinavir/ritonavir monotherapy, compared with triple ARV regimens, recent data on switch strategy to DRV/r monotherapy, in patients with sustained virologic suppression have demonstrated noninferior efficacy.

New antiretroviral classes: rationale & potential for their use in HIV-infected patients affected by comorbidities have been addressed

Integrase inhibitor: Given its neutral effect on lipids, raltegravir (RGV) may represent a valuable option in patients affected by cardiovascular diseases. Its safety and efficacy in a switch strategy from PI-based regimens has been tested in two trials, with good results in terms of lipid profiles but conflicting data on virologic efficacy. RGV represents an option for new NRTI-sparing regimens, as demonstrated by trials evaluating the efficacy and tolerability of RGV plus ATV/r.
CCR5 antagonist: The use of maraviroc may have potential additional benefits resulting from its mechanism of action: the CCR5 receptor has been involved in the pathogenesis of atherosclerosis and of HIV-associated osteoporosis. These are rationale premises for its use in patients affected by comorbidities, but no data are available. Maraviroc may also represent an option for NRTI-sparing regimens.

Conclusion

The alternative ARV strategies explored to date have some limitations and do not completely satisfy the clinical need.
Clinical studies focused on new drugs are emerging, but only preliminary findings are available. Further data need to be generated in order to provide valuable alternative therapeutic regimens for patients affected by severe comorbidities.

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