Non-whites comprise the vast majority of individuals living with HIV disease worldwide. According to UNAIDS-WHO, out of a total of 33.2 million people with HIV infection in 2007, 22.5 million lived in Sub-Saharan Africa. In the U.S., increasing numbers of African Americans and Hispanics/Latinos are HIV-infected compared with other racial/ethnic groups. African Americans comprise 13% of the total U.S. population, but represent 45% of new HIV/AIDS diagnoses; Hispanics make up 14% of the U.S. population, and account for 17% of new HIV infections.

Virological and immunological status at the time of clinical presentation, as well as response to combination antiretroviral therapy, may vary by race/ethnicity. However, prior studies have concluded that race/ethnicity does not have a major effect on the outcome of HAART in HIV patients.

Lopinavir/ritonavir (Kaletra) soft-gel capsules (SGC) dosed once-daily (QD) or twice-daily (BID) for 48 weeks, along with once-daily tenofovir (Viread) plus emtricitabine (Emtriva) have shown similar virological and immunological efficacy regardless of race [1].

In the current study (M05-730), presented at the XVII International AIDS Conference last week in Mexico City (August 3-8, 2008), researchers assessed virological response, CD4 cell increases, adverse events (AEs), and laboratory abnormalities of non-white vs white antiretroviral-naive patients taking lopinavir/ritonavir tablets in combination with tenofovir and emtricitabine.

This ongoing 96-week, Phase 3, open label, randomized, multicenter, international study enrolled 664 antiretroviral-naive patients with HIV RNA > 1000 copies/mL and any CD4 cell count. Participants were randomized 1:1:1:1 to receive one of 4 lopinavir/ritonavir regimens: QD SGC, BID SGC, QD tablet, or BID tablet for 8 weeks. All participants also received 200 mg QD emtricitabine and mg QD tenofovir. At week 8, all subjects receiving the SGC switched to the tablet formulation while maintaining their same randomized dosing schedule (QD or BID).

Participants were evaluated every 2 weeks through week 16, every 8 weeks through week 48, and then every 12 weeks through week 96.

The primary efficacy endpoint was the proportion of patients with HIV RNA < 50 copies/m/L at week 48, using an intent-to-treat (ITT, NC=F) approach comparing QD and BID groups. Secondary analyses included the mean change form baseline in CD4 count and the emergence of viral resistance through 48 weeks.

Race/ethncity was determined by the participant's selection among the choices white, black, Asian, American Indian/Alaska Native, or other. Participants were included as white if they selected only white; all others were includes as non-white. There were 165 non-white participants. The majority were black; the rest were Asian (12.1%), American Indian/Alaskan Native (3.6%), and other (10.9%).

The investigators compared 48-week safety and efficacy between participants self-reporting as white vs non-white with respect to virological response, CD4 cell increase, adverse events, and laboratory abnormalities.

Therapy preference for participants who switched from the SGC to tablet formulation at week 8 was also assessed. Participants were asked to choose which formulation they preferred: Kaletra tablets, Kaletra soft gel capsules, or equal preference for tablets and soft gel capsules.

Results

• Overall, in the primary efficacy analysis at week 48, 77% of QD-treated and 76% of BID-treated patients achieved a viral load < 50 copies/mL by ITT, NC=F analysis.

• The difference in response rates (QD minus BID) was 1% (CI -5% to 8%), which confirmed the non-inferiority of the QD regimen to the BID regimen.

• Overall, similar mean increases from baseline in CD4 cell counts at week 48 were observed in the QD and BID treatment groups (186 and 197 cells/mm3, respectively; p = 0.350).

• Mean baseline CD4 counts were significantly different between white (224.7 cells/mm3) and non-white (187.6 cells/mm3) participants (p = 0.002).

• The mean baseline HIV RNA was higher in white participants (5.03 log10 copies/mL) compared with non-white patients (4.88 log10 copes/mL) (p = 0.014).

• Mean baseline low-density lipoprotein (LDL or "bad") cholesterol levels were lower in non-whites compared with whites (p = 0.007).

• There were no statistically significant differences between non-white and white participants with regard to reasons for treatment discontinuation.

• There was no difference in the overall proportion of white and non-white participants achieving HIV RNA < 50copies/mL at week 48: 77% vs 75.2%, respectively (p = 0.672).

• In addition, there were no differences between whites and non-whites in virological response at week 48 when stratifying participants by baseline CD4 cell count or baseline viral load (<100,000 or > 100,000 copies/mL).

• There was no difference in mean increase in CD4 cell count at week 48 between non-white and white participants: 185 vs 194 cells/mm3, respectively (p = 0.495).

• Mean increases in CD4 count at week 48 were similar between racial groups regardless of baseline CD4 count.

• Gastrointestinal (GI) adverse events were the most commonly occurring events in both white and non-white subjects.

• 2 GI events occurred in > 5% of the participants in all race/dose groups.

• One AE -- anorexia (loss of appetite) -- was noted in a significantly higher proportion of non-white compared with white participants (p = 0.049); this, however, occurred in only a small percentage of the study cohort (1.8% and 0.2%, respectively).

• The overall rate of moderate to severe diarrhea was approximately 16%; white participants experienced moderate to severe diarrhea at a rate of 17.8%, while non-whites experienced moderate to severe diarrhea less frequently at 9.7% (p = 0.014).

• No statistically significant differences were noted between white and non-white participants, overall and within the QD or BID groups with regard to mean changes from baseline to week 48 in total cholesterol, triglycerides, LDL, or LDL to high-density lipoprotein (HDL or "good") cholesterol (LDL:HDL) ratio.

• Statistically significant differences were noted for HDL between white and non-white participants overall (p = 0.001), for QD dosing (p = 0.007), and for BID dosing (p = 0.018).

• At week 48, there were no significant differences between racial/ethnic groups in terms of grade 3/4 abnormalities of transaminases (liver enzymes), total cholesterol, triglycerides, or creatinine clearance regardless of dosing regimen.

• The patient preference questionnaire administered at week 12 showed that both white and non-white participants who switched from the SGC to the tablet formulation at week 12 overwhelmingly preferred the tablet.

• Among participants who switched from the SGC to the tablet at week 8, 78% of non-whites and 77% of whites preferred the tablet over the SGC (p < 0.001 for both).

• Only 3% of non-whites and 5% of whites preferred the SGC over the tablet.

Summary

• There was no difference in the efficacy of a lopinavir/ritonavir-based regimen dosed QD or BID at 48 weeks in antiretroviral-naive non-white vs white participants.

• In addition, as was noted for the overall population, within sub-groups defined by baseline CD4 count and baseline HIV RNA levels, similar proportions of non-white and white participants achieved HIV RNA < 50 copies/mL at week 48.

• Within subgroups defined by baseline CD4 count, mean CD4 cell increases at week 48 were similar for non-white and white participants.

• Despite having lower baseline HIV viral loads, non-white participants had lower baseline CD4 counts compared with white participants (mean 188 vs 335 cells/mm3, respectively; p = 0.002).

• Previous data report that non-white individuals tend to present later for HIV testing and treatment; as a result, these patients may have lower CD4 counts at clinical presentation. While later presentation may explain the lower CD4 cell counts, the potential for lower HIV viral loads are less clear.

• Lopinavir/ritonavir was well tolerated in both non-white and white participants.

• The overall rate of moderate to severe diarrhea for the study was approximately 16%. Given that white males comprise the majority of the study population, it is not surprising that they experienced moderate to severe diarrhea rates similar to the overall study population; however, non-white subjects experienced moderate to severe diarrhea less frequently than whites.

• Mean baseline LDL cholesterol levels were lower in non-whites compared with whites. At week 48, mean change in triglycerides, total cholesterol, and LDL was similar for non-whites and whites, with no mean increase in the LDL:HDL for either group. Non-whites had a significantly greater mean increase in HDL compared with whites.

• Both non-white and white participants overwhelmingly preferred the tablet form of lopinavir/ritonavir over the SGC.

• The reasons associated with patient preference were not collected, but may include the lack of refrigeration, diminished food affect, and possible tolerability effects not detected by the standardized adverse event assessment during a clinical trial.

• Data from this study are consistent with previous studies that demonstrated patient preference for the tablet formulation after switching from the SGC.

Conclusions

Based on these findings, the investigators concluded that lopinavir/ritonavir-based regimens dosed once- or twice-daily provide similar virological efficacy and immunological recovery in both non-white and white patient, regardless of baseline CD4 count or viral load.

Further, they noted, "the lopinavir/ritonavir safety profile was similar between races for both QD and BID dosing."

Finally, they stated, "The patient preference questionnaire demonstrated that subjects overwhelmingly preferred the tablet formulation over the SGC, regardless of race."

Abbott Laboratories, North Chicago, IL.

8/12/08

Reference
B da Silva, D Cohen, S Gibbs, and others. Comparable HIV-1 Viral Suppression and Immunologic Recovery of White and Non-white Antiretroviral-naive Subjects Taking Lopinavir/ritonavir (LPV/r) Tablets + Tenofovir Disoproxil Fumarate (TENOFOVIR) and Emtricitabine (FTC) through 48 Weeks. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Poster TUPE0063.

Other citation
1. P Esterbrook and others. Antiretroviral Therapy in Special Populations: response to Lopinavir/ritonavir, Tenofovir DF, and Emtricitabine in ARV-naïve Patients by Gender, Race/ethnicity, and Hepatitis CO-infection Status. 7th International Congress on Drug Therapy in HIV Infection. Glasgow, UK. 2004