Discussion
This study reports our observations of lipid changes following switch from first-line ART to second-line regimens containing new classes of antiretroviral drugs with a view to making recommendations on lipid level measurement during second-line ART in an African setting. It should be noted that the DART study (DART) was conducted at a time when triple- nucleoside regimens were in vogue and hence second-line regimens contained a combination of boosted-PIs and NNRTI with or without the addition of NRTIs.
It is well established that increased TC, LDL-C, TC/HDL-C ratio and TG are associated with an increased risk of cardiovascular events, while raised HDL-C reduces this risk [
18]. These observations have been made in large studies that indicate these associations to hold across all ethnicities [
20]. Observations in resource-rich countries show that HIV infection is associated with low serum lipid levels depending on degree of immunosuppression and viraemia [
6,
7]. Several studies in African settings have made similar observations on patients before ART initiation [
21‐
24]. ART has transformed the lives of HIV infected patients but changes in lipid levels are a recognised complication of ART [
6,
9,
25]. Although the belief is that Africans in sub-Saharan Africa generally have low lipid levels, there is evidence that this is changing in response to many factors including urbanization with changes in diet, low exercise level and increasing prevalence of hypertension, diabetes and smoking [
26].
At baseline (switch to second-line ART after a median of 2.2 years of first-line ART) the TC, LDL-C and TG levels in our study participants were low which is consistent with a low atherogenic risk [
18]. The HDL-C levels were however low reflecting a high atherogenic risk. The combination of low TC and low HDL-C resulted in a TC/HDL-C ratio of 4.9 which is reflective of a borderline [
18], but relatively high atherogenic risk if one considers the generally low TC and LDL-C levels. After ≥48 weeks of second-line ART predominantly consisting of a combination of PI/r and NNRTI with or without NRTIs there was a marked increase in lipid levels; relative increases of TC 59%, LDL-C 61%, HDL-C 71% and TG 29%. The TC/HDL-C ratio remained unchanged because of the marked increase in HDL-C. Women had a greater increase in LDL-C than men. Older patients had greater increases in TC, LDL-C and HDL-C. Those with higher BMI had greater increases in TG, and smaller increases in HDL-C than those with lower BMI.
In a South African study of 42 patients on an NNRTI-based first-line regimen the TC, LDL-C, HDL-C and TG levels (mean ± standard deviation) following 2.1 years of first-line ART exposure were; 4.75 ± 1.24, 2.65 ± 0.97 and 1.41 ± 0.42 and 1.20 ± 1.18 respectively [
13]. In contrast in our patients after 2.2 years of first-line ART (ie at switch to second-line ART); TC, LDL-C and HDL-C levels were lower but TG was higher than in the South African study. The difference could, at least in part, be explained by the lower proportion of women in our study than in the South African study, 48% vs 64% respectively. Indeed there were other important differences between our two studies. Our patients were predominantly on a triple-nucleoside first-line regimen (86%) while the South African patients were all on an NNRTI regimen. However, in a Ugandan study of 374 patients (49% women) who were on a predominantly NNRTI-based first-line regimen (98% on NVP), lipid levels (mmol/L) after 2 years were; 3.91; 2.05; 1.22; 1.35; and 3.4 for TC, LDL-C, HDL-C, TG and TC/HDL-C ratio respectively [
14], again TC, LDL-C and HDL-C higher than values at switch to second-line in our Zimbabwean study, but lower than in South Africa. Of note, HDL-C at switch to second-line ART was markedly low in the Zimbabwean study. Interestingly TG levels were more similar in all three studies.
The lipid levels in this Zimbabwean African population are generally low after exposure to a predominantly triple nucleoside first-line ART regimen. The choice of second-line regimens which mostly contained both PI/r and NNRTIs in our study was dictated by first-line exposure. It is therefore not possible to fully ascribe lipid changes to either the PI/r or NNRTI class of antiretroviral drugs, given the small number of patients not receiving NNRTI second-line. PI-based regimens have been associated with elevated lipid levels in several studies [
5,
9,
27], although the setting of such changes is often complex [
7]. In a study in Benin a significant increase in TC was observed in a cohort of 88 patients who were on an NNRTI first-line regimen [
28]. Several studies have shown that NNRTI based regimens are associated with elevated TC and LDL-C levels [
8,
9,
28] with regimens combining PIs and NNRTIs showing higher degrees of dyslipidaemia [
8]. Various members of the PI class have been shown to have varying effects on lipid changes. In a South African study, after 48 weeks of first-line ART, there was a smaller rise in LDL-C level with an Atazanavir based regimen compared to a Nelfinavir based regimen. Indeed in comparison to Nelfinavir, Atazanvir exposure was not associated with clinically relevant increases in TC, LDL-C or TG. Another limitation of our study is that we did not have a sufficient numbers of patients on EFV versus those on NVP to allow comparison of the impact of these two NNRTIs on lipid change. The percentage increases in TC, HDL-C and TG were high, but because of relatively low baseline levels at switch to second-line ART, the levels attained after exposure to second-line ART were modest.
In this study an almost equal number of men and women of similar ages were recruited which gives us the opportunity to compare lipid changes between men and women unlike studies in resource-rich countries which have predominantly studied men. The fact that women had higher lipid levels than men at switch and 48 weeks later is difficult to explain since normally men have higher athrogenic lipids than women [
18]. A partial explanation may be the higher BMI in females compared to males. Indeed both men and women had similar degrees of immunosuppression as shown by similar CD4 counts.
Because of the generally low level of lipids in African populations the facilities to perform lipid assays are limited and expensive. It may therefore not be possible to give a recommendation on routine monitoring of lipids, or even how often lipid levels should be monitored in this population. This preliminary study suggests that lipid changes do occur over the short-to-medium term on second-line LPV/r containing regimens, but are generally mild abnormalities, and are at least partially offset (in terms of cardiovascular risk) by increases in HDL-C, furthermore our results are limited by the short follow-up period. The best approach for the time being may, therefore, be to recommend assessment of total atherogenic risk ie risk factors such as smoking, hypertension, diabetes, BMI and family history to guide monitoring for and indeed treatment of lipids in individual patients. We await further studies to provide more general guidelines on the monitoring and management of lipids during ART based on risk factors for cardiovascular disease, and the impact of various classes of antiretroviral drugs or individual agents.
Acknowledgements
We thank all the patients and staff from all the centres participating in the DART trial.
MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda: H Grosskurth, P Munderi, G Kabuye, D Nsibambi, R Kasirye, E Zalwango, M Nakazibwe, B Kikaire, G Nassuna, R Massa, K Fadhiru, M Namyalo, A Zalwango, L Generous, P Khauka, N Rutikarayo, W Nakahima, A Mugisha, J Todd, J Levin, S Muyingo, A Ruberantwari, P Kaleebu, D Yirrell, N Ndembi, F Lyagoba, P Hughes, M Aber, A Medina Lara, S Foster, J Amurwon, B Nyanzi Wakholi, K Wangati, B Amuron, D Kajungu, J Nakiyingi, W Omony, K Fadhiru, D Nsibambi, P Khauka.
Joint Clinical Research Centre, Kampala, Uganda: P Mugyenyi, C Kityo, F Ssali, D Tumukunde, T Otim, J Kabanda, H Musana, J Akao, H Kyomugisha, A Byamukama, J Sabiiti, J Komugyena, P Wavamunno, S Mukiibi, A Drasiku, R Byaruhanga, O Labeja, P Katundu, S Tugume, P Awio, A Namazzi, GT Bakeinyaga, H Katabira, D Abaine, J Tukamushaba, W Anywar, W Ojiambo, E Angweng, S Murungi , W Haguma, S Atwiine, J Kigozi, L Namale. A Mukose, G Mulindwa, D Atwiine, A Muhwezi, E Nimwesiga, G Barungi, J Takubwa, S Murungi, D Mwebesa, G Kagina, M Mulindwa, F Ahimbisibwe, P Mwesigwa, S Akuma, C Zawedde, D Nyiraguhirwa, C Tumusiime, L Bagaya, W Namara, J Kigozi, J Karungi, R Kankunda, R Enzama.
University of Zimbabwe, Harare, Zimbabwe: A Latif, J Hakim, V Robertson, A Reid, E Chidziva, R Bulaya-Tembo, G Musoro, F Taziwa, C Chimbetete, L Chakonza, A Mawora, C Muvirimi, G Tinago, P Svovanapasis, M Simango, O Chirema, J Machingura, S Mutsai, M Phiri, T Bafana, M Chirara, L Muchabaiwa, M Muzambi, E Chigwedere, M Pascoe, C Warambwa, E Zengeza, F Mapinge, S Makota, A Jamu, N Ngorima, H Chirairo, S Chitsungo, J Chimanzi, C Maweni, R Warara, M Matongo, S Mudzingwa, M Jangano, K Moyo, L Vere, I Machingura.
Infectious Diseases Institute (formerly the Academic Alliance) Makerere University, Mulago, Uganda: E Katabira, A Ronald, A Kambungu, F Lutwama, I Mambule, A Nanfuka, J Walusimbi, E Nabankema, R Nalumenya, T Namuli, R Kulume, I Namata, L Nyachwo, A Florence, A Kusiima, E Lubwama, R Nairuba, F Oketta, E Buluma, R Waita, H Ojiambo, F Sadik, J Wanyama, P Nabongo, J Oyugi, F Sematala, A Muganzi, C Twijukye, H Byakwaga.
The AIDS Support Organisation (TASO), Uganda: R Ochai, D Muhweezi, A Coutinho, B Etukoit.
Imperial College, London, UK: C Gilks, K Boocock, C Puddephatt, C Grundy, J Bohannon, D Winogron.
MRC Clinical Trials Unit, London, UK: J Darbyshire, DM Gibb, A Burke, D Bray, A Babiker, AS Walker, H Wilkes, M Rauchenberger, S Sheehan, C Spencer-Drake, K Taylor, M Spyer, A Ferrier, B Naidoo, D Dunn, R Goodall.
Independent DART Trial Monitors: R Nanfuka, C Mufuka-Kapuya.
DART Virology Group: P Kaleebu (Co-Chair), D Pillay (Co-Chair), P Awio, M Chirara, D Dunn, DM Gibb, C Gilks, R Goodall, A Kapaata, M Katuramur, F Lyagoba, R Magala, B Magambo, K Mataruka, A McCormick, L Mugarura, T Musunga, M Nabankkema, J Nkalubo, P Nkurunziza, C Parry, V Robertson, M Spyer, D Yirrell.
Trial Steering Committee: I Weller (Chair), A Babiker (Trial Statistician), S Bahendeka, M Bassett, A Chogo Wapakhabulo, J Darbyshire, B Gazzard, C Gilks, H Grosskurth, J Hakim, A Latif, C Mapuchere, O Mugurungi, P Mugyenyi; Observers: C Burke, M Distel, S Jones, E Loeliger, P Naidoo, C Newland, G Pearce, S Rahim, J Rooney, M Smith, W Snowden, J-M Steens.
Data and Safety Monitoring Committee: A Breckenridge (Chair), A McLaren (Chair-deceased), C Hill, J Matenga, A Pozniak, D Serwadda.
Endpoint Review Committee: T Peto (Chair), A Palfreeman, M Borok, E Katabira.