The two NRTIs generally used as first-line drugs are 3TC and either AZT or d4T (which are antagonistic and should not be prescribed together). Zidovudine can cause anemia or worsen it where malnutrition or other chronic diseases such as TB and malaria are endemic. On the other hand, while d4T may be safer as an initial therapeutic agent for anemic patients, it has been associated with higher rates of neuropathy and lipodystrophy. While lowering the d4T dose may prevent progression of these side effects, AZT may be a better long-term option once anemia is controlled. 3TC is used in all first-line (and many second-line) regimens because it is the best tolerated antiretroviral drug and has no significant drug-drug interactions. Moreover, the 184 mutation that develops with 3TC may result in a virus that is in fact less fit than the native (wild-type) virus.

Abacavir, ddI, or TDF can also be paired with 3TC to form the nucleoside backbone of the ART regimen. However, ddI is less tolerated than other NRTIs. Abacavir and TDF are very potent drugs and generally well tolerated, but generic equivalents are not available at the time of this writing. Thus, these medications remain very expensive for inclusion in first-line therapy, and they are recommended for use in second-line therapy.

Due to its safety profile in pregnant women, its generic availability, and its low cost, NVP is the most common third agent in first-line therapy. As described in Section 2.5.5, however, several studies and recent data from the manufacturer suggest that women with a CD4 count above 250 cells/mm³ experience a much higher risk of hepatitis from NVP than either men or women with low CD4 counts. Thus, women with a CD4 count above 250 cells/mm³ who are receiving NVP should have their LFTs monitored one week after initiation of therapy and every two weeks subsequently (or earlier and more frequently if symptoms of hepatitis occur). ²

Efavirenz is indicated as the third agent for patients who are intolerant of NVP (due to rash or hepatitis). Additionally, patients who are being treated for TB with a regimen containing rifampin should receive EFV instead of NVP, as described in Section 2.4.4, as levels of both NVP and R are lowered in the presence of the other drug. Concomitant administration of EFV will not alter the blood level of R, and increasing the EFV dose to 800 mg/day will counter the effect that R has on the blood level of EFV. Note that EFV is teratogenic and should not be prescribed for women who are pregnant or not practicing birth control.

The most common first- and second-line antiretroviral regimens as recommended by the WHO are summarized in Table 3.1.

Table 3.1 Recommended First- and Second-Line ART Regimens for Adults and Adolescents

Regimen		Components
	NRTI	NRTI	NNRTI or PI
First-line regimen	AZT or d4T	3TC	NVP or EFV
Second-line regimen	TDF	ABC, 3TC, or AZT/3TC	LPV/RTV