**7. Switching antiviral therapies**

initially suggested that lipoatrophy in HIV-1 patients is primarily associated with the use of PI-based therapies; however, more recent reports show that the incidence of lipoatrophy was significantly higher in the efavirenz plus two NRTIs group than in the lopinavir or efavirenz plus two NRTIs plus lopinavir groups [85-87]. The association of lipoatrophy with efavirenz use was mainly in combination with either stavudine or zidovudine but not with tenofovir/ lamivudine. Lipohypertrophy consists of the accumulation of adipose tissue. The PI-based therapy has been associated with the development of lipohypertrophy, but several longitudi‐ nal studies have failed to demonstrate that this therapy is the main cause of lipohypertrophy

**Drug class Drug Effects on lipids Effects on glucose**

↑ Dyslipidemia ↑ ↑ Dyslipidemia ↑ Dyslipidemia ↑ Dyslipidemia ↑ ↑ Dyslipidemia ↑ Dyslipidemia ↑ ↑ Dyslipidemia

↑ ↑ HDL, ↑ Dyslipidemia

Neutral effects ↑ ↑ HDL, ↑ LDL Neutral effect

↑ ↑ ↑ Dyslipidemia ↑ Dyslipidemia ↑ Dyslipidemia ↑ ↑ ↑ Dyslipidemia ↑ ↑ Dyslipidemia ↑ ↑ ↑ Dyslipidemia ↑ ↑ Dyslipidemia ↑ Dyslipidemia ↑ ↑ ↑ Dyslipidemia

Neutral effect Neutral effect Neutral effect No effect Insulin resistance No effect No effect Insulin resistance No effect Insulin resistance

No effect No effect

No effect No effect No effect

Insulin resistance Insulin resistance Insulin resistance Insulin resistance Insulin resistance Insulin resistance Insulin resistance Insulin resistance Insulin resistance

in HIV-1 patients [86-89].

NRTIs Abacavir (ABC)

NNRTIs Efavirenz (EFV)

PIs Amprenavir/ritonavir

InSTIs Dolutegravir (DTG)

Didanozine (ddl) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT)

138 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

Etravirine (ETR) Nevirapine (NVP) Rilpivirine (RPV)

Atazanavir/ritonavir Darunavir/ritonavir Fosamprenavir/ritonavir

Lopinavir/ritonavir Nelfinavir Saquinavir

Tipranavir/ritonavir

Elvitegravir (EVG) Raltegravir (RAL)

**Table 2.** Antiretroviral drugs: impact on lipid and glucose metabolism.

Fusion inhibitors Enfuvirtide, T-20 Neutral effect No effect

Entry inhibitors Selzentry Neutral effect No effect

Indinavir

The search for different therapeutic strategies to reverse HAART-associated dyslipidemia has led to the use of less metabolically active antiretroviral drugs without compromising antire‐ troviral efficacy. Ritonavir is the most representative drug in HAART-associated dyslipidemia and in combination with lopinavir confers higher risks for cardiovascular disease in HIV-1 patients. Amprenavir and nelfinavir promote lower impacts compared to the therapy with lopinavir/ritonavir [31, 70, 80, 90, 91]. Similarly, the use of indinavir and saquinavir shows even less adverse effect on lipid metabolism in HIV-1 patients receiving HAART. Currently, atazanavir has the least impact on lipid metabolism [92, 93]. In contrast, nelfinavir promotes the elevation of TC, TG and LDL levels, and its replacement by atazanavir permits the reduction of the concentrations of these parameters without affecting antiretroviral activity [94]. A more recent alternative is tipranavir, a non-peptide PI prescribed for patients with multidrug resistance (MDR). However, this drug has shown deleterious effects that promote atherogenic risk by increasing the levels of TC and TG [95]. Another strategy to control dyslipidemia has been the discontinuation of the PI-based regimens and a switch to a NRTIor NNRTI-based protocol. For ART-naïve patients, HAART regimens that include at least one NNRTI, or abacavir and two NRTIs, might be as efficient as PI-based therapy, although they may not be the standard choice. This exchange of HAART in patients with viral suppression did not reduce antiretroviral efficacy during long-term use [95-96]. A strategy that must be better evaluated is the long-term use of the NRTI/NNRTI class of drugs before the use of PIbased therapy. The use of NRTI-associated nevirapine reduces levels of TC and TG, promotes an increase in HDL and a decrease in atherogenic risk. The use of NNRTIs may also alter the lipid profile due mostly to the use of efavirenz. Using this medication, TG levels were higher when compared with nevirapine usage. However, in studies with a large number of HIV-1 patients, accompanied at intervals of ninety days and with undetectable HIV-1-RNA, the levels of TC, LDL and TG were kept within the desirable limit in the groups treated with nevirapine and efavirenz, including HDL levels within the reference values [95-98]. Only the HIV-1 patients treated with a PI-based regimen showed lipid abnormalities and increased risks for cardiovascular disease [13, 24, 96]. In addition, possible alterations in lipid metabolism resulting from the use of NNRTI-based therapy are easier and faster to reverse with the use of statins, fibrates, diet and lifestyle. Although the individual effects of NRTIs remain unclear, stavudine was associated with TC and TG elevations greater than zidovudine and tenofovir. The addition of fusion inhibitors to the existing therapies, such as enfuvirtide/T-20, had little effect on plasma lipids. The possibility of different HAART strategies eliminating or reducing the dyslipidemia in HIV-1 patients must be evaluated, and the risk of development of variants of the virus with MDR must be taken into account [99]. In HIV-1 patients with favorable historical responses to HAART and accompanied by a physician experienced in HIV-1 infection, the transition from a PI-based to a therapy with nevirapine, abacavir, or even atazanavir may be preferable to the use of a hypolipidemic agent. In practice, many patients will show pre-existing resistance to the drugs, limiting options for the exchange of the treatment [83, 92-94]. Experts must assess the risks of toxicity of the new treatment and the possibility of virologic relapse when switching HAART regimens.
